N-substituted aminoalkanephosphinic acid derivatives, compositions thereof, and their use as anti-epileptics

ABSTRACT

Compounds having GABAB-antagonistic properties, for example those of formula I   &lt;IMAGE&gt; (I)  wherein one of the radicals R1, R2 and R3 is hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another is hydrogen or, in the case of R1 or R2, hydroxy or, in the case of R1, halogen or, in the case of R2 together with R2&#39;, oxo, and the remaining radical is hydrogen, R1&#39; is hydrogen or halogen, R2&#39; is hydrogen, hydroxy or, together with R2, is oxo, R4 and R5 are hydrogen or R4 is an araliphatic or heteroarylaliphatic radical and R5 is hydrogen or an aliphatic radical, and R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heteroarylaliphatic or aromatic radical having at least 2 carbon atoms or, when R1 is hydrogen or hydroxy, R2 is an aromatic radical and R1&#39;, R2&#39; and R3 are hydrogen. R is methyl, and their pharmaceutically acceptable salts, can be used as active ingredients in medicaments for the treatment of epilepsies of the &#34;petit mal&#34; type. The invention relates also to novel compounds of formula I and processes for the preparation thereof.

This is a divisional of Ser. No. 056,726, filed May 3rd, 1993, now U.S.Pat. No. 5,407,922, which is a divisional of Ser. No. 718,503, filedJun. 20th, 1991, now U.S. Pat. No. 5,229,379.

The invention relates to the use of compounds having GABA_(B)-antagonistic properties as anti-epileptics for the treatment ofepilepsies of the "petit mal" type and for suppressing "petit mal"-typeconditions which may arise in the case of treatment with knownanti-epileptics, and for the preparation of an anti-epileptic for thetreatment of epilepsies of the "petit mal" type, to anti-epilepticmedicaments comprising those compounds and a process for the preparationof such medicaments, and to a method, characterised by theadministration of such a medicament, of treating epileptic disorders ofthe "petit mal" type and of suppressing "petit mal"-type conditionswhich may arise in the case of treatment with known anti-epileptics, andalso to novel compounds having GABA_(B) -antagonistic properties, toprocesses for the preparation thereof and to pharmaceutical compositionscomprising them.

Compounds having GABA_(B) -antagonistic properties are to be understoodas being compounds that are able to bind to GABA_(B) -receptors and acton them as antagonists of GABA (γ-aminobutyric acid). They are, forexample, compounds of formula I ##STR2## wherein one of the radicals R₁,R₂ and R₃ is hydrogen or an aliphatic, cycloaliphatic, araliphatic oraromatic radical, another is hydrogen or, in the case of R₁ or R₂,hydroxy or, in the case of R₁, halogen or, in the case of R₂ togetherwith R₂ ', oxo, and the remaining radical is hydrogen, R₁ ' is hydrogenor halogen, R₂ ' is hydrogen, hydroxy or, together with R₂, is oxo, R₄and R₅ are hydrogen or R₄ is an araliphatic or heteroarylaliphaticradical and R₅ is hydrogen, an an aliphatic radical or a group R₄, and Ris an aliphatic, cycloaliphatic, cycloaliphatic,cycloaliphatic-aliphatic, araliphatic, heteroarylaliphatic or aromaticradical having at least 2 carbon atoms or, when R₁ is hydrogen orhydroxy, R₂ is an aromatic radical and R₁ ', R₂ ' and R₃ are hydrogen. Ris methyl, and their pharmaceutically acceptable salts, can be used

Novel compounds having GABA_(B) -antagonistic properties are especiallyaraliphatically N-substituted aminoalkanephosphinic acids of formula Iwherein R₁, R₁ ', R₂ ' and R₃ are hydrogen, R₂ is hydrogen or hydroxy,R₄ is an araliphatic radical other than unsubstituted 1-phenyl-loweralkyl, or is a heteroarylaliphatic radical, R₅ is hydrogen, lower alkylor a group R₄, and R is an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic radical having at least 2 carbonatoms, and their pharmaceutically acceptable salts.

Aliphatic radicals R are, for example, lower alkyl having at least 2carbon atoms, lower alkenyl, lower alkynl, oxo-lower alkyl, hydroxy- ordihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di- orpoly-halo-lower alkyl, mono-, di or poly-halo-lower alkenyl, mono-, di-or poly-halo(hydroxy)-lower alkyl, mono-, di- orpoly-halo(hydroxy)-lower alkenyl, lower alkoxy-lower alkyl, di-loweralkoxy-lower alkyl, lower alkoxy(hydroxy)-lower alkyl, loweralkoxy(halo-lower alkyl, lower alkylthio-lower alkyl and di-loweralkylthio-lower alkyl. Aliphatic radicals R₁, R₂ and R₃ are especiallylower alkyl, including and especially methyl, lower alkenyl or loweralkynl.

Cycloaliphatic radicals are, for example, cycloalkyl, and in the case ofcycloaliphatic radical R they are also hydroxycycloalkyl, oxa-, dioxa-,thia and dithia-cycloalkyl.

Cycloaliphatic-aliphatic radicals are, for example, cycloalkyl-loweralkyl, cycloalkenyl-lower alkyl, mono-, di- ortrihydroxycycloalkyl-lower alkyl, cycloalkyl(hydroxy)-lower alkyl and(lower alkylthio)cycloalkyl(hydroxy)-lower alkyl.

Araliphatic radicals are, for example, mono- or di-phenyl-lower alkyl ornaphthyl-lower alkyl each of which is unsubstituted or mono-, di ortri-substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or bytrifluoromethyl, preferably α-phenyl-lower alkyl substituted asindicated or unsubstituted α,α-diphenyl- or α-naphthyl-lower alkyl.

Heteroarylaliphatic radicals are, for example, thienyl-, furyl- orpyridyl-lower alkyl each of which is unsubstituted or substituted,especially mono- or di-substituted, by halogen, preferably unsubstitutedα-thienyl, α-furyl- or α-pyridyl-lower alkyl.

Aromatic radicals are, for example, phenyl, which in the case ofaromatic radicals R₁, R₂ and R₃ is preferably substituted, for exampleby halogen, lower alkyl, lower alkoxy and/or by trifluoromethyl,especially monosubstituted by halogen, and also naphthyl.

Hereinbefore and hereinafter, lower radicals and compounds are to beunderstood as being, for example, radicals and compounds having up toand including 7, preferably up to and including 4, carbon atoms (Catoms).

Lower alkyl R is, for example C₂ -C₇ alkyl, preferably C₃ -C₅ alkyl,such as propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl orpentyl, but may also be a C₆ -C₇ alkyl group, such as a hexyl or heptylgroup.

Lower alkyl R₅ is, for example, C₁ -C₇ alkyl, preferably C₁ -C₄ alkyl,such as methyl, ethyl, propyl, isopropyl or butyl, but may also beiso-butyl, sec-butyl, tert-butyl or a C₅ -C₇ alkyl group, such as apentyl, hexyl or heptyl group.

Lower alkenyl is, for example, C₂ -C₄ alkenyl, such as vinyl, allyl orbut-2-enyl, but may also be a C₅ -C₇ alkenyl group, such as pentenyl,hexenyl or heptenyl.

Lower alkynl is, for example, C₂ -C₇ alkynl, preferably C₃ -C₅ alkynl,that carries the double bond in a position higher than the α,β-position,for example 2-propynyl (propargyl), but-3-yn-1-yl, but-2-yn-1-yl orpent3-yn-1-yl.

Oxo-lower alkyl carries the oxo group preferably in a position higherthan the α-position and is, for example, oxo-C₂ -C₇ alkyl, especiallyoxo-C₃ -C₆ alkyl, such as 2-oxopropyl, 2- or 3-oxobutyl or 3-oxopentyl.

Hydroxy-lower alkyl carries the hydroxy groups preferably in the α- orβ-position and is, for example, corresponding hydroxy-C₂ -C₇ alkyl, suchas 1-hydroxyethyl, 1- or 2-hydroxypropyl, 2-hydroxyprop-2-yl, 1- or2-hydroxybutyl, 1-hydroxyisobutyl or 2-hydroxy-3-methylbutyl.

Dihydroxy-lower alkyl carries the hydroxy groups especially in theα,β-position and is, for example, α,β-dihydroxy-C₃ -C₇ alkyl, such as1,2-hydroxyprop-2-yl.

Hydroxy-lower alkenyl carries the hydroxy groups preferably in theα-position and the double bond preferably in a position higher than theα,β-position and is, for example, corresponding α-hydroxy-C₃ -C₅alkenyl, for example 1-hydroxybut-2-enyl.

Mono-, di- or poly-halo-lower alkenyl is, for example, mono-, di- ortri-fluoro-C₂ -C₅ alkenyl, such as 1-fluorobut-2-enyl.

Mono-, di- or tri-halo(hydroxy)-lower alkyl carries the hydroxy grouppreferably in the α-position and the halogen atoms preferably in aposition higher than the α-position and is, for example, correspondingmono-, di- or tri-fluoro-α-hydroxy-C₂ -C₇ alkyl, such as4,4,4-trifluoro-1-hydroxybutyl.

Mono-, di- or poly-halo-lower alkyl is, for example, mono, di- ortri-fluoro-C₂ -C₅ alkyl, such as 3,3,3-trifluoropropyl,4,4,4-trifluorobutyl, 1- or 2-fluorobutyl or 1,1-difluorobutyl. Loweralkoxy is, for example, C₁ -C₇ alkoxy, preferably C₁ -C₄ alkoxy, such asmethoxy, ethoxy, propoxy, isopropoxy or butoxy, but may also beisobutyoxy, sec-butoxy, tert-butoxy or a C₅ -C₇ alkoxy group, such as apentyloxy, hexyloxy or heptyloxy group.

Mono-, di- or tri-halo(hydroxy)-lower alkenyl carries the hydroxy grouppreferably in the α-position and the halogen atoms preferably in aposition higher than the α-position and is, for example, correspondingmono, di- or tri-fluoro-α-hydroxy-C₂ -C₅ alkenyl, such as2-fluoro-1-hydroxybuten-2-yl.

Lower alkoxy-lower alkyl is, for example, C₁ -C₄ alkoxy-C₁ -C₄ alkyl,such as methoxy- or ethoxy-methyl, 2-methoxyethyl, 2-ethoxyethyl,3-methoxy- or 3-ethoxy-propyl or 1- or 2-methoxybutyl.

Di-lower alkoxy-lower alkyl is, for example, di-C₁ -C₄ alkoxy-C₁ -C₄alkyl, for example dimethoxymethyl, dipropoxymethyl, 1,1- or2,2-diethoxyethyl, diisopropoxymethyl, dibutoxymethyl or3,3-dimethoxypropyl.

Lower alkoxy(hydroxy)-lower alkyl is, for example, C₁₋₄ alkoxy-C₂ -C₅(halo)-lower alkyl, such as 2-fluoro-3-methoxybutyl.

Lower alkylthio-lower alkyl is, for example, C₁ -C₄ alkylthio-C₁ -C₄alkyl, such as methylthio- or ethylthio-methyl, 2-methylthioethyl,2-ethylthioethyl, 3-methylthio- or 3-ethylthio-propyl or 1- or2-methylthiobutyl.

Di-lower alkylthio-lower alkyl is, for example, di-C₁ -C₄ alkylthio-C₁-C₄ alkyl, for example dimethylthiomethyl, dipropylthiomethyl, 1,1- or2,2-diethylthioethyl, diisopropylthiomethyl, dibutylthiomethyl or3,3-dimethylthiopropyl.

Mono- or di-phenyl-lower alkyl is, for example, mono- or di-phenyl-C₁-C₄ alkyl, such as benzyl, 1- or 2-phenylethyl or 2-phenylprop-2-yl,diphenylmethyl or, secondly, 2-phenylethyl, 2-phenylprop-1-yl or3-phenylprop-1-yl.

Naphthyl-lower alkyl is, for example, naphthyl-C₁ -C₄ alkyl, such as 1-or 2-naphthylmethyl.

Thienyl-, furyl- or pyridyl-lower alkyl is, for example, thienyl-,furyl- or pyridyl-methyl, 1thienyl-, 1-furyl- or 1-pyridyl-ethyl,2-thienyl-, 2-furyl- or 2-pyridyl-prop-2-yl, or, secondly, 2-thienyl-,2-furyl- or 2-pyridyl-ethyl, 2-thienyl-, 2-furyl- or 2-pyridyl-prop-1-ylor 3-thienyl-, 3-furyl- or 3-pyridyl-prop-1-yl.

Halogen is, for example, halogen having an atomic number of up to andincluding 53, such as chlorine, iodine or fluorine, and also bromine.

Cycloalkyl is, for example, C₃ -C₈ cycloalkyl, especially C₃ -C₆ alkyl,such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Hydroxycycloalkyl is, for example, α-hydroxy-C₃ -C₆ cycloalkyl, such as1-hydroxycyclopropyl, 1-hydroxycyclobutyl or 1-hydroxycyclohexyl.

Oxa- or thia-cycloalkyl is, for example, oxa- or thia-C₃ -C₈ cycloalkyl,especially oxa- or thia-C₃ -C₆ cycloalkyl, such as 2-oxacyclopropyl(oxiranyl), 2- or 3-oxacyclobutyl (oxetanyl), 2- or 3-thiacyclobutyl(thietanyl), 2- or 3-oxacyclopentyl (tetrahydrofuranyl), 2- or3-thiacyclopenyl (thiolanyl) or 2-oxacyclohexyl (tetrahydropyranyl).

Dioxacycloalkyl is, for example, 1,3-dioxa-C₃ -C₈ cycloalkyl, such as1,3-dioxolan-2-yl or 1,3-dioxan-2-yl.

Dithiacycloalkyl is, for example, 1,3-dithia-C₃ -C₈ cycloalkyl, such as1,3-dithiolan-2-yl or 1,3-dithian-2-yl.

Cycloalkyl-lower alkyl is, for example, C₃ -C₈ cycloalkyl-C₁ -C₄ alkyl,especially C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl, such as α-(C₃ -C₆cycloalkyl)-C₁ -C₄ alkyl, for example cyclopropylmethyl,cyclopbutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Cycloalkenyl-lower alkyl is, for example, C₃ -C₈ -, especially C₃ -C₆cycloalkenyl-C₁ -C₄ alkyl, such as α-(C₃ -C₆ cycloalkenyl)-C₁ -C₄ alkyl,for example cyclohex-3-enyl.

Mono-, di- or trihydroxycycloalkyl-lower alkyl is, for example, mono-,di- or trihydroxy-C₃ -C₈, especially mono, di- or trihydroxy-C₃ -C₆cycloalkyl-C₁ -C₄ alkyl, such as α-(mono-, di- or trihydroxy-C₃ -C₆cycloalkyl)-C₁ -C₄ alkyl, for example 3,4-dihydroxycyclohexylmetnyl or3,4,5-trihydroxycyclohexylmethyl.

Cycloalkyl(hydroxy)-lower alkyl is, for example, C₃ -C₆ cycloalkyl-C₁-C₆ (hydroxy) alkyl, such as α-(C₃ -C₆ cycloalkyl-α-hydroxy-C₁ -C₄alkyl, for example cyclopropyl(hydroxy)methyl, cyclobutyl(hydroxy)methylor cyclohexl(hydroxy)methyl.

(Lower alkylthiocycloalkyl)(hydroxy-lower alkyl is, for example, 1-(C₁-C₄ alkylthio-C₃ -C₆ cycloalkyl)-1-hydroxy-C₁ -C₄ alkyl, such as(2-methylthiocycloprop-1-yl)hydroxymethyl.

On account of their amphoteric nature, the compounds of formula I are inthe form of internal salts and can form acid addition salts and saltswith bases.

Acid addition salts of compounds of formula I are, for example,pharmaceutically acceptable salts thereof with suitable mineral acids,such as hydrohalic acids, sulfuric acid or phosphoric acid, for examplehydrochlorides, hydrobromides, sulfates, hydrogen sulfates orphosphates, or salts with suitable aliphatic or aromatic sulfonic acidsor N-substituted sulfamic acids, for example methanesulfonates,benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfaminates(cyclamates).

Salts of compounds of formula I with bases are, for example, saltsthereof with pharmaceutically acceptable bases, such as non-toxic metalsalts derived from metal of groups Ia, Ib, IIa and IIb, for examplealkali metal salts, especially sodium or potassium salts, alkaline earthmetal salts, especially calcium or magnesium salts, and also ammoniumsalts with ammonia or organic amines or quarternary ammonium bases, suchas unsubstituted or C-hydroxylated aliphatic amines, especially mono-,di- or tri-lower alkylamines, for example methyl-, ethyl- ordiethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)amines, such asethanol-, diethanol- or triethanol-amine, tris(hydroxymethyl)methylamineor 2-hydroxy-tert-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-loweralkylamines or N-(polyhydroxy-lower alkyl-lower alkylamines, such as2-(dimethylamino-ethanol or D-glucamine, or quaternary aliphaticammonium hydroxides, for example tetrabutylammonium hydroxide.

Depending upon the presence of asymmetric carbon atoms, the compoundsaccording to the invention may be in the form of isomeric mixtures,especially of racemates, or in the form of pure isomers, especially ofoptical antipodes.

Compounds of formula I wherein one of the radical R₁, R₂ and R₃ ishydrogen or an aliphatic, cycloaliphatic, araliphatic or aromaticradical, another is hydrogen or, in the case of R₁ or R₂, hydroxy, andthe remaining radical is hydrogen, and wherein R₁ ', R₂ ', R₄ and R₅ arehydrogen, and their pharmaceutically acceptable salts and their GABA_(B)-antagonistic properties, are known and have already been proposed asnootropic, anxiolytic and anti-depressive active ingredients inmedicaments.

The novel compounds of formula I and their pharmaceutically acceptablesalts also have valuable GABA_(B) -antagonistic properties. Inparticular, they exhibit effective binding to the GABA_(B) -receptor andprove to be antagonists of GABA (γ-aminobutyric acid) at that receptor.From the point of view of mechanism, antagonism to GABA_(B) -receptorscan increase the release of rapid stimulus amino acid transmitters, thatis to say glutamate and aspartate, and thus improve the processing ofinformation in the brain. In line with this is the discovery that thelate postsynaptic inhibition potential in the hippocampus, which isattributed to a GABA_(B) -mechanism, is broken down by the antagonistsand thus allows a more rapid nerve impulse transmission sequence.

On the other hand, it has been found that chronic treatment withanti-depressants and repeated electric shocks increases the number ofGABA_(B) -receptors in the cerebral cortex of rats. In accordance withreceptor theories, chronic treatment with GABA_(B) -antagonists shouldproduce the same effect. For this and other reasons, therefore, GABA_(B)-antagonists can act as anti-depressants.

The novel GABA_(B) -antagonists according to the invention interact atthe GABA_(B) -receptor with IC₅₀ values of approximately 10⁻⁸ M(moles/l) and above in cerebral cortex membranes of rats. In contrast toGABA_(B) -agonists such as baclofen, they do not potentiate thestimulation of adenylate cyclase by noradrenalin in sections of ratcerebral cortex, but act as an antagonist to the action of baclofen. Theantagonism to baclofen can also be demonstrated in vitro inelectrophysiological models, for example in penicillin-induced"epileptic" hippocampus section preparation, where baclofen in aconcentration of 6 μM (micromoles/litre) inhibits "epilepsy-like"discharges of pyramidal cells. The compounds according to the inventionact as an antagonist to baclofen action at concentrations of fromapproximately 10 to approximately 100 μM (micromoles/litre). In vivo,the antagonism can be demonstrated by iontophoresis of baclofen in thecerebral cortex of rats and by systemic administration of antagonists indoses of from 10 to 100 mg/kg. At doses of approximately 30 mg/kg,antagonism to the muscle-relaxing action of baclofen occurs, which ismeasured in the Rotarod model.

The novel GABA_(B) -antagonists not only exhibit antagonism to baclofen,but also exhibit an independent action as antagonists to endogenousGABA. Accordingly, the antagonists are active in conventional behavioralmodels which are characteristic of anti-depressive, anxiolytic and/ornootropic properties. It has been found that compounds of formula I areactive on oral administration in the floating test according to Porsolt,in the Geller test, the delayed passive avoidance test (single-attemptmodification) in pre-test and post-test situations, in the two-chambertest and in the complex labyrinth. Moreover, in studies on Rhesusmonkeys an increased play instinct, curiosity, social grooming behaviorand a reduction in anxiety symptoms were observed.

The novel compounds of formula I and their pharmaceutically acceptablesalts are therefore excellently suitable as nootropics, anti-depressantsand anxiolytics, for example for the treatment of symptoms of cerebralinsufficiency, emotional depression and anxiety conditions.

On account of the antagonism of the known GABA_(B) -antagonists tobaclofen, it has hitherto been assumed that GABA_(B) -antagonists, suchas compounds of formula I, do not have an anti-epileptic activitycomponent.

Surprisingly, it has now been found that GABA_(B) -antagonists,especially compounds of formula I, have pronounced anti-absenceproperties in vivo.

These properties can be demonstrated in a particular strain of rats onthe basis of their pronounced inhibitory action on spontaneous "spikeand wave" discharges in the following animal model for absence epilepsy.

Approximately 30% of the Wistar rats reared at the Centre de Neurochimiein Strasbourg exhibit spontaneous changes in behaviour, of whichelectroencephalograms (EEG) and symptoms are comparable to those ofhuman absences (petit mal). Synchronous "spike and wave" discharges(SWD; frontoparietal cortex; 7-8 Hz; 300-1000 μV, duration 0.5 to 40 s,mean value=60±3.4 s) and frequently myoclonia facialis accompany acessation of behaviour. These absence-like condition occur spontaneouslyand repeatedly. By selective rearing of these rates it was possible toobtain a strain in which 100% of the rats exhibit these SWD (epilepticrats). In contrast, a strain could be reared in which 100% of the ratsare SWD-free (control rats). This pharmacological model is described inVergnes M., Marescaux C., Micheletti G., Reis J., Depaulis A., RumbackL. and Warter J. M., Neurosci. Lett. 33, 97-101 (1982).

In this model, for example, the clinically used anti-epilepticsethosuximide, diazepam, trimethadione and sodium valproate in does ≧50mg/kg (trimethadione and sodium valproate) in doses ≧25 mg/kg(ethosuximide), ≧0.5 mg/kg (diazepam) and ≧50 mg/kg (trimethadione andsodium valproate) reduce the spike and wave discharge in dose-dependentmanner. Carbamazepine and phenytoin are ineffective or make the attacksworse at high doses. Phenobarbital is effective at from 2.5 to 10 mg/kgand is ineffective at 20 mg/kg. The action of these anti-epileptics onthe crises in rats and absences in humans supports the hypothesis thatthis animal model represents a pharmacological model for absenceepilepsy. Its predictive value appears to be at least as good as that ofother customary animal models.

The compounds of formula I and their pharmaceutically acceptable salts,as well as being suitable as nootropics, anti-depressants andanxiolytics, are therefore excellently suitable as active ingredients inanti-epileptic medicaments for the treatment of epilepsies of the "petitmal" type, both of spontaneous absence epilepsies, such as spontaneousabsence epilepsies in children and young people, and atypical absences,such as absences of the Lennox-Gastaut syndrome, and also of absencesthat occur of undesired side effects in the case of treatment withconventional "grand mal" anti-epileptics, such as phenytoin,carbamazepine or Vigabatrin® and anti-epileptics having the same or asimilar activity profile.

The invention relates, for example, to the use of compounds of formula Iwherein

a) R₁ and R₁ ' are hydrogen, R₂ is an aliphatic, cycloaliphatic,araliphatic or aromatic radical and R₂ ' is hydrogen or hydroxy, or ₂ ishydroxy and R₂ ' is hydrogen, or R₂ and R₂ ' together form an oxo group,and R₃, R₄ and R₅ are hydrogen, or

b) R₁ is hydroxy or an aliphatic, cycloaliphatic, araliphatic oraromatic radical and R₁ ', R₂, R₂ ', R₃, R₄ and R₅ are hydrogen, or

c) R₁ is halogen, R₁ ' is hydrogen or halogen and R₂, R₂ ', R₃, R₄ andR₅ are hydrogen.

wherein R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,araliphatic or aromatic radical having at least 2 carbon atoms, or whenR₁ is hydrogen or hydroxy, R₂ is an aromatic radical and R₁ ', R₂ ' andR₃ are hydrogen, R is methyl, and their pharmaceutically acceptablesalts as anti-epileptic and for the preparation of an anti-epileptic forthe treatment of epilepsies of the "petit mal" type, to anti-epilepticmedicaments comprising those compounds and a process for the preparationof such medicaments, and to a method, characterised by theadministration of such a medicament, of treating epileptic disorders ofthe "petit mal" type.

The invention relates especially to the use of compounds of formula Iwherein one of the radicals R₁, R₂ and R₃ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, or phenyl-lower alkyl,diphenyl-lower alkyl or naphthyl-lower alkyl each of which isunsubstituted or mono- or poly-substituted in the phenyl or naphthylmoiety by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl,or phenyl or naphthyl each of which is unsubstituted or substituted byhalogen, lower alkyl, lower alkoxy and/or by trifluoromethyl, anotherradical is hydrogen or, in the case of R₁ or ₂, hydroxy or, in thefluoromethyl, another radical is hydrogen or, in the case of R₁ or R₂,hydroxy or, in the case of R₁, halogen or, in the case of R₂ togetherwith R₂ ', oxo, and the remaining radical is hydrogen, R₁ ' is hydrogenor halogen, R₂ ' is hydrogen, hydroxy or, together with R₂, is oxo, R₄and R₅ are hydrogen, of R₄ is phenyl-lower alkyl, diphenyl-lower alkyl,naphthyl-lower alkyl, thienyl-lower alkyl, furyl-lower alkyl orpyridyl-lower alkyl each of which is unsubstituted or mono- orpoly-substituted in the phenyl, naphthyl, thienyl, furyl or pyridylmoiety by lower alkyl, lower alkoxy, halogen and/or by trifluoromethyl,and R₅ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or a groupR₄, and R is lower alkyl having at least 2 carbon atoms, lower alkenyl,lower alkynyl, cycloalkyl, cycloalkyl-lower alkyl, cycloalkenyl-loweralkyl, mono-, di- or trihydroxycycloalkyl-lower alkyl,cycloalkyl(hydroxy)-lower alkyl, (loweralkylthio-cycloalkyl(hydroxy)-lower alkyl, or phenyl- or naphthyl-loweralkyl each of which is unsubstituted or mono- or poly-substituted in thephenyl or naphthyl moiety by lower alkyl, lower alkoxy, halogen and/orby trifluoromethyl, or phenyl or naphthyl each of which is unsubstitutedor substituted by halogen, lower alkyl, lower alkoxy and/or bytrifluoromethyl, or, when R₁ is hydrogen or hydroxy, R₂ is an aromaticradical and R₁ ', R₂ ' and R₃ are hydrogen, R is methyl, and theirpharmaceutically acceptable salts as anti-epileptics for the treatmentof epilepsies of the "petit mal" type and for suppressing "petitmal"-type conditions arising from known anti-epileptics, and for thepreparation of an anti-epileptic for the treatment of epilepsies of the"petit mal" type, to anti-epileptic medicaments comprising thosecompounds and a process for the preparation of such medicaments, and toa method, characterised by the administration of such a medicament, oftreating epileptic disorders of the "petit mal" type and of suppressingthe mentioned "petit mal"-type conditions arising from knownanti-epileptics, and also to compounds of formula I wherein R₁, R₁ ', R₂' and R₃ are hydrogen, R₂ is hydrogen or hydroxy, R₄ is a phenyl-,diphenyl- or naphthyl-lower alkyl radical each of which is unsubstitutedor mono-, di or tri-substituted in the phenyl or naphthyl moiety bylower alkyl, lower alkoxy, hydroxy and/or by halogen, or is a thienyl-,furyl- or pyridyl-lower alkyl radical each of which is unsubstituted orhalo-substituted in the thienyl, furyl or pyridyl moiety, R₅ ishydrogen, lower alkyl or a group R₄, and R is lower alkyl having atleast 2 carbon atoms, lower alkenyl, lower alkynyl, oxo-lower alkyl,hydroxy- or dihydroxy-lower alkyl, hydroxy-lower alkenyl, mono-, di orpoly-halo-lower alkyl, mono-, di- or poly-halo-lower alkenyl, mono-, di-or poly-halo(hydroxy)-lower alkyl, mono-, di- orpoly-halo(hydroxy)-lower alkenyl, lower alkoxy-lower alkyl, di-loweralkoxy-lower alkyl, lower alkoxy(hydroxy)-lower alkyl, loweralkoxy(halo)-lower alkyl, lower alkylthio-lower alkyl, di-loweralkylthio-lower alkyl, cycloalkyl, hydroxycycloalky, oxa-, dioxa-, thia-and dithia-cycloalkyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl,mono-, di or trihydroxycycloalkyl-lower alkyl, cycloalkyl(hydroxy)-loweralkyl and (lower alkylthio)cycloalkyl(hydroxy)-lower alkyl, or mono- ordi-phenyl-lower alkyl or naphthyl-lower alkyl each of which isunsubstituted or mono-, di- or tri-substituted by lower alkyl, loweralkoxy, halogen, hydroxy and/or by trifluoromethyl, or unsubstituted orhalo-substituted thienyl-, furyl- or pyridyl-lower alkyl, and theirsalts, especially their pharmaceutically acceptable salts, as such.

The invention relates especially, for example, to the use of compoundsof formula I wherein

a) R₁ and R₁ ' are hydrogen, R₂ is an aliphatic, cycloaliphatic,araliphatic or aromatic radical and R₂ ' is hydrogen or hydroxy, or ₂ ishydroxy and R₂ ' is hydrogen, or R₂ and R₂ ' together form an oxo group,and R₃, R₄ and R₅ are hydrogen, or

b) R₁ is hydroxy or an aliphatic, cycloaliphatic, araliphatic oraromatic radical and R₁ ', R₂, R₂ ', R₃, R₄ and R₅ are hydrogen, or

c) R₁ is halogen, R₁ ' is hydrogen or halogen and R₂, R₂ ', R₃, R₄ andR₅ are hydrogen.

wherein R is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,araliphatic or aromatic radical having at least 2 carbon atoms or, whenR₁ is hydrogen or hydroxy, R₂ is an aromatic radical and R₁ ', R₂ ' andR₃ are hydrogen, R is methyl, and their pharmaceutically acceptablesalts as anti-epileptic and for the preparation of an anti-epileptic forthe treatment of epilepsies of the "petit mal" type, to anti-epilepticmedicaments comprising those compounds and a process for the preparationof such medicaments, and to a method, characterised by theadministration of such a medicament, of treating epileptic disorders ofthe "petit mal" type, and also to compounds of formula I wherein R₁, R₁', R₂ ' and R₃ are hydrogen, R₂ is hydrogen or hydroxy, R₄ is a phenyl-or naphthyl-lower alkyl radical each of which is unsubstituted orsubstituted by lower alkyl, lower alkoxy and/or by halogen, or anunsubstituted or halo-substituted thienyl-, furyl- or pyridyl-loweralkyl radical, R₅ is hydrogen, lower alkyl or a group R₄, and R is loweralkyl having at least 2 carbon atoms, lower alkenyl, lower alkynyl,oxo-lower alkyl, hydroxy- or dihydroxy-lower alkyl, hydroxy-loweralkenyl, mono-, di- or poly-halo-lower alkyl, mono- di- orpoly-halo-lower alkenyl, mono-, di- or poly-halo(hydroxy)-lower alkyl,mono-, di- or poly-halo(hydroxy)-lower alkenyl, lower alkoxy-loweralkyl, di-lower alkoxy-lower alkyl, lower alkoxy(hydroxy)-lower alkyl,lower alkoxy(halo)-lower alkyl, lower alklthio-lower alkyl, di-loweralkylthio-lower alkyl, cycloalkyl, hydroxycycloalkyl, oxa-, dioxa-,thia- and dithia-cycloalkyl, cycloalkyl(hydroxy)-lower alkyl and (loweralkylthio)cycloalkyl(hydroxy)-lower alkyl, or phenyl-lower alkyl ornaphthyl-lower alkyl each of which is unsubstituted or mono- ordi-substituted by lower alkyl, lower alkoxy, halogen, and/or bytrifluoromethyl, and their salts, especially their pharmaceuticallyacceptable salts.

The invention relates more especially to the use of compounds of formulaI wherein one of the radicals R₁, R₂ and R₃ is hydrogen, C₁ -C₄ alkyl,C₃ -C₆ alkyloalkyl, phenyl- or naphthylC₁ -C₄ alkyl that isunsubstituted or mono- or poly-substituted in the phenyl or naphthylmoiety by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen and/or bytrifluoromethyl, or is phenyl or naphthyl either of which isunsubstituted or mono- or poly-substituted in the phenyl or naphthylmoiety by C₁ -C₄ alkyl, C_(1-C) ₄ alkoxy, halogen and/or bytrifluoromethyl, another radical is hydrogen or, in the case of R₁ orR₂, hydroxy, and the remaining radical is hydrogen, R₁ ' is hydrogen, R₂' is hydrogen, hydroxy or, together with R₂, is oxo, R₄ and R₅ arehydrogen, or R₄ is a phenyl-C₁ -C₄ alkyl radical that is unsubstitutedor mono- or poly-substituted in the phenyl moiety by C₁ -C₄ alkyl, C₁-C₄ alkoxy, halogen and/or by trifluoromethyl, and R₅ is hydrogen, C₁-C₄ alkyl or a group R₄, and R is C₂ -C₇ alkyl, α,α-di-C₁ -C₄ alkoxy-C₂-C₇ alkyl, α, α-dihalo-C₂ -C₇ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆cycloalkyl-C₁ -C₄ alkyl, C₃ -C₆ cycloalkenyl-C₃ -C₄ alkyl, such as α-(C₃-C₆ cycloalkenyl)-C₁ -C₄ alkyl, for example, cyclohex-3-enyl, mono-, di-or trihydroxy-C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl, such as α-(mono-, di- ortrihydroxy-C₃ -C₆ cycloalkyl)-C₁ -C₄ alkyl, for example,3,4-dihydroxycyclohexylmethyl or 3,4,5-trihydroxycyclohexylmethyl,benzyl or, when R₂ is halophenyl and R₁, R₁ ', R₂ ' and R₃ are hydrogen,R is methyl, and their pharmaceutically acceptable salts asanti-epileptics for the treatment of epilepsies of the "petit mal" typeand for suppressing "petit mal"-type conditions arising from knownanti-epileptics, and for the preparation of an anti-epileptic for thetreatment of epilepsies of the "petit mal" type, to anti-epilepticmedicaments comprising those compounds and a process for the preparationof such medicaments, and to a method, characterised by theadministration of such a medicament, of treating epileptic disorders ofthe "petit mal" type and of suppressing the mentioned "petit mal"-typeconditions arising from known anti-epileptics, and also to compounds offormula I wherein R is C₃ -C₇ alkyl, such as propyl, isopropyl, butyl,isobutyl or pentyl, α,α-di-C₁ -C₄ alkoxy-C₁ -C₄ alkyl, especiallyα,α-di-C₁ -C₄ alkoxymethyl, such as dimethoxy- or diethoxy-methyl, C₃-C₆ cycloalkyl-C₁ -C₄ alkyl, such as cyclopropyl- or cyclohexyl-methyl,C₃ -C₆ cycloalkenyl-C₁ -C₄ alkyl, such as α-(C₃ -C₆ cycloalkenyl)-C₁ -C₄alkyl, for example, cyclohex-3-enyl, mono-, di- or trihydroxy-C₃ -C₆cycloalkyl-C₁ -C₄ alkyl, such as α-(mono-, di- or trihydroxy-C₃ -C₆cycloalkyl)-C₁ -C₄ alkyl, for example, 3,4-dihydroxycyclohexylmethyl or3,4,5-trihydroxycyclohexylmethyl, or benzyl that is unsubstituted ormono-, di- or tri-substituted by C₁ -C₄ alkyl, such as methyl, C₁ -C₄alkoxy, such as methoxy, hydroxy and/or by halogen, such as fluorine,chlorine or iodine, R₁ is hydrogen or hydroxy, R₂ is phenyl- ordiphenyl-C₁ -C₄ alkyl, such as benzyl, 1-phenylethyl or2-phenylprop-2-yl, each of which is unsubstituted or mono-, di- ortri-substituted by C₁ -C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, such asmethoxy, and/or by halogen, such as fluorine, chlorine or iodine, or isnapthtyl-C₁ -C₄ alkyl, such as 1- or 2-naphthylmethyl, thienyl-C₁ -C₄alkyl, such as thienylmethyl, furyl-C₁ -C₄ alkyl, such as furylmethyl,or pyridyl-C₁ -C₄ alkyl, such as pyridylmethyl, each of which isunsubstituted or monosubstituted by halogen having an atomic number ofup to and including 35, such as chlorine, and R₃ is hydrogen, C₁ -C₄alkyl, such as methyl, or a group R₂, and their salts, especially theirpharmaceutically acceptable salts, as such.

The invention relates more especially to the use, for example, ofcompounds of formula I wherein

a) R₁ and R₁ ', R₂ ', R₃, R₄ and R₅ are hydrogen, R₂ is C₁ -C₄ alkyl, C₃-C₆ cycloalkyl, benzyl, phenyl, halophenyl or naphthyl and R₂ ' ishydrogen or hydroxy, or R₂ is hydroxy and R₂ 'is hydrogen, or R₂ and R₂' together form an oxo group, or

b) R₁ is hydroxy, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, benzyl, phenyl,halophenyl or naphthyl, and R₁ ', R₂, R₃, R₄ and R₅ are hydrogen, or

c) R₁ is halogen, R₁ ' is hydrogen or halogen and R₂, R₂ ', R₃, R₄ andR₅ are hydrogen, and

R is C₂ -C₇ alkyl, α,α-di-C₁ -C₄ alkoxy-C₂ -C₇ alkyl, α,α-dihalo-C₂ -C₇alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl, benzyl or,when R₂ is halophenyl or naphthyl and R₁, R₁ ', R₂ ' and R₃ arehydrogen, R is methyl, and their pharmaceutically acceptable salts asanti-epileptics and for the preparation of an anti-epileptic for thetreatment of epilepsies of the "petit mal" type, to anti-epilepticmedicaments comprising those compounds and a process for the preparationof such medicaments, and to a method, characterised by theadministration of such a medicament, of treating epileptic disorders ofthe "petit mal" type, and also to compounds of formula I wherein R₁, R₁', R₂ ' and R₃ are hydrogen, R₂ is hydrogen or hydroxy, R₄ is phenyl-C₁-C₄ alkyl, such as benzyl, 1-phenylethyl or 2-phenylprop-2-yl, that isunsubstituted or monosubstituted by C₁ -C₄ alkyl, such as methyl, or C₁-C₄ alkoxy, such as methoxy, or mono- or di-substituted by halogenhaving an atomic number of up to and including 35, such as chlorine, oris naphthyl-, thienyl-, furyl- or pyridyl-C₁ -C₄ alkyl, such as 1- or2-naphthyl-, thienyl-, furyl- or pyridyl-methyl, each of which isunsubstituted or monosubstituted by halogen having an atomic number ofup to and including 35, such as chlorine, R₅ is hydrogen, C₁ -C₄ alkyl,such as methyl, or a group R₄, and R is C₃ -C₇ alkyl, such as propyl,isopropyl, butyl, isobutyl or pentyl, α,α-di-C₁ -C₄ alkoxy-C₁ -C₄ alkyl,especially α,α-di-C₁ -C₄ alkoxymethyl, such as dimethoxy- ordiethoxy-methyl, C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl, such as cyclopropyl- orcyclohexyl-methyl, or benzyl that is unsubstituted of substituted by C₁-C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, such as methoxy, or by halogenhaving an atomic number of up to and including 35, such as chlorine, andtheir salts, especially their pharmaceutically acceptable salts, assuch.

The invention relates very especially to the use of compounds of formulaI wherein R₁, R₁ ', R₂ ' and R₃ are hydrogen, R₂ is hydrogen or hydroxy,R₄ and R₅ are hydrogen, or R₄ is a phenyl-C₁ -C₄ alkyl radical, such asa benzyl radical, that is unsubstituted or mono- or poly-substituted inthe phenyl moiety by C₁ -C₄ alkyl, such as methyl, C₁ -C₄ alkoxy, suchas methoxy, halogen, such as chlorine, and/or by trifluoromethyl, and R₅is hydrogen or C₁ -C₄ alkyl, such as methyl or ethyl, and R is C₂ -C₇alkyl, such as butyl, α,α-C₁ -C₄ alkoxy-C₁ -C₄ alkyl, such asdiethoxymethyl, α,α-dihalo-C₂ -C₇ alkyl, such as 1,1-difluorobutyl, C₃-C₆ cycloalkyl, such as cyclohexyl, C₃ -₆ cycloalkyl-C₁ -C₄ alkyl, suchas cyclohexylmethyl, or is a phenyl-C₁ -C₄ alkyl radical, such as abenzyl or 1-phenylethyl radical, that is unsubstituted or mono- orpoly-substituted in the phenyl moiety by C₁ -C₄ alkyl, such as methyl,C₁ -C₄ alkoxy, such as methoxy, halogen, such as chlorine, and/or bytrifluoromethyl, and their pharmaceutically acceptable salts asanti-epileptics for the treatment of epilepsies of the "petit mal" typeand for suppressing "petit mal"-type conditions arising from knownanti-epileptics, and for the preparation of an anti-epileptic for thetreatment of epilepsies of the "petit mal" type, to anti-epilepticmedicaments comprising those compounds and a process for the preparationof such medicaments, and to a method, characterised by theadministration of such a medicament, of treating epileptic disorders ofthe "petit mal" type and of suppressing the mentioned "petit mal"-typeconditions arising from known anti-epileptics, and also to compounds offormula I wherein R₁, R₁ ', R₂ ' and R₃ are hydrogen, R₂ is hydrogen orhydroxy, R₄ is α-phenyl-C₁ -C₄ alkyl, such as benzyl, 1-phenylethyl or2-phenylprop-2-yl, that is unsubstituted or mono- or di-substituted byhalogen having an atomic number of up to and including 35, such aschlorine, or is unsubstituted α-naphthyl-C₁ -C₄ alkyl, such as 1- or2-naphthylmethyl, α-thienyl-C₁ -C₄ alkyl, such as thienylmethyl,α-furyl-C₁ -C₄ alkyl, such as furylmethyl, or α-pyridyl-C₁ -C₄ alkyl,such as pyridylmethyl, R₅ is hydrogen, C₁ -C₄ -alkyl, such as methyl, ora group R₄, and R is C₃ -C₅ alkyl, such as butyl, α,α-di-C₁ -C₄alkoxymethyl, such as diethoxymethyl, C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl,such as cyclopropyl- or cyclohexyl-methyl, C₃ -C₆ -cycloalkenyl-C₁ -C₄alkyl, such as α-(C₃ -C₆ cycloalkenyl)-C₁ -C₄ alkyl, for example,cyclohex-3-enyl, mono-, di- or trihydroxy-C₃ -C₆ cycloalkyl-C₁ -C₄alkyl, such as α-(mono-, di- or trihydroxy-C₃ -C₆ -cycloalkyl)-C₁ -C₄alkyl, for example, 3,4-dihydroxycyclohexylmethyl or3,4,5-trihydroxycyclohexylmethyl, or benzyl, and their salts, especiallytheir pharmaceutically acceptable salts, as such.

The invention relates very especially, for example, to the use ofcompounds of formula I wherein R₁, R₁ ', R₂ ', R₃, R₄ and R₅ arehydrogen, R₂ is hydrogen or hydroxy and R is C₂ -C₇ alkyl, α,α-di-C₁ -C₄alkoxy-C₁ -C₄ alkyl, such as diethoxymethyl, α,α-dihalo-C₂ -C₇ alkyl,such as 1,1-difluorobutyl, C₃ -C₆ cycloalkyl, such as cyclohexyl, C₃ -C₆-cycloalkyl-C₁ -C₄ alkyl, such as cyclohexylmethyl, or benzyl, and theirpharmaceutically acceptable salts as anti-epileptics and for thepreparation of an anti-epileptic for the treatment of epilepsies of the"petit mal" type, to anti-epileptic medicaments comprising thosecompounds and a process for the preparation of such medicaments, and toa method, characterised by the administration of such a medicament, oftreating epileptic disorders of the "petit mal" type, and also tocompounds of formula I wherein R₁, R₁ ', R₂ ' and R₃ are hydrogen, R₂ ishydrogen or hydroxy, R₄ is phenyl-C₁ -C₄ alkyl, such as benzyl,1-phenylethyl or 2-phenylprop-2-yl, that is unsubstituted or mono- ordi-substituted by halogen having an atomic number of up to and including35, such as chlorine, or is unsubstituted naphthyl-, thienyl-, furyl- orpyridyl-C₁ -C₄ alkyl, such as 1- or 2-naphthyl-, thienyl-, furyl- orpyridyl-methyl, R₅ is hydrogen, C₁ -C₄ alkyl, such as methyl, or a groupR₄, and R is C₃ -C₅ alkyl, such as butyl, α,α-di-C₁ -C₄ alkoxymethyl,such as diethoxymethyl, C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl, such ascyclopropyl- or cyclohexyl-methyl, or benzyl, and their salts,especially their pharmaceutically acceptable salts, as such.

The invention relates specifically to the use of the known compoundslisted below:

3-aminopropyl(cyclohexylmethyl)phosphinic acid,

3-aminopropyl(n-butyl)phosphine acid,

3-aminopropyl(diethoxymethyl)phosphinic acid,

3-aminopropyl(benzyl)phosphinic acid,

3-aminopropyl(1,1-difluorobutyl)phosphinic acid,

3-amino-2-(p-chlorophenyl)propyl(methyl)phosphinic acid,

3-amino-2-hydroxypropyl(cyclohexylmethyl)phosphinic acid,

3-amino-2(S)-hydroxypropyl(cyclohexylmethyl)phosphinic acid,

3-amino-2(R)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid and

3-amino-2(S)-hydroxypropyl(benzyl)phosphinic acid

and their pharmaceutically acceptable salts as anti-epileptics and forthe preparation of an anti-epileptic for the treatment of epilepsies ofthe "petit mal" type, to anti-epileptic medicaments comprising thosecompounds and a process for the preparation of such medicaments, and toa method, characterised by the administration of such a medicament, oftreating epileptic disorders of the "petit mal" type, and also to thecompounds mentioned in the Preparation Examples, specifically

3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid,

3-(p-chlorobenzylamino)-2-(S)-hydroxypropyl(benzyl)phosphinic acid,

3-(p-chlorobenzylamino)-2-hydroxypropyl(n-butyl)phosphinic acid,

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(benzyl)phosphinic acid,

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(diethoxymethyl)phosphinicacid, and

3-(p=chlorobenzylamino)propyl(cyclohexylmethyl)phosphinic acid

and their pharmaceutically acceptable salts, as such.

The process for the preparation of the novel araliphaticallyN-substituted aminoalkanephosphinic acids of formula I provided inaccordance with the invention comprises, in a compound of formula II##STR3## wherein R₁, R₁ ', R₂ ' and R₃ are hydrogen, R₆ is ahydroxy-protecting group, R₈ is a group R₅ or an amino-protecting groupand R₁₀ is hydrogen or protected hydroxy, and R, R₁, R₄ and R₅ are asdefined above, or in a salt thereof, freeing the hydroxy groups byreplacing the hydroxy-protecting group R₆ by hydrogen and, whereappropriate, removing the amino-protecting group R₈ and, whereappropriate, freeing the hydroxy groups R₂ from the protected hydroxygroup R₁₀, and, if desired, converting a resulting compound into adifferent compound of formula I, separating a mixture of isomersobtainable in accordance with the process into the components andseparating the preferred isomer, and/or converting a free compoundobtainable in accordance with the process into a salt or converting asalt obtainable in accordance with the process into the correspondingfree compound.

Protected hydroxy groups R₆ O are, for example, etherified hydroxygroup, preferably hydroxy groups etherified by an aliphatic,cycloaliphatic, araliphatic or aromatic alcohol or by a silanol, suchas, especially, lower alkoxy, lower alkenyloxy, phenyloxy orphenylalkoxy, such as benzyloxy, each of which is unsubstituted orsubstituted, for example, by lower alkyl, lower alkoxy, halogen and/orby nitro, or tri-lower alkylsilyloxy, such as trimethylsilyloxy,tributylsilyloxy or tert-butyl(dimethyl)silylxoy.

The protecting group R₆ in the compounds of formula II can be replacedby hydrogen by treatment with a suitable basic or acid agent, such as analkali metal hydroxide, for example sodium hydroxide or lithiumhydroxide, an alkali metal halide, especially an alkali metal bromide oriodide, such as lithium bromide or sodium iodide, thiourea, an alkalimetal thiophenolate, such as sodium thiophenolate, or a protonic orLewis acid, such as a mineral acid, for example hydrochloric acid, or atri-lower alkylhalosilane, for example trimethylchlorosilane. Theexchange reaction can be carried out in the absence or presence of asolvent and, if necessary, with heating or with cooling, in a closedvessel and/or under an inert gas atmosphere.

The replacement of the R₆ protecting group, for example a silyl or alkylgroup, in compounds of formula II by hydrogen can, however, also beeffected by treatment with an acid under hydrolytic conditions,especially with a mineral acid, such as a hydrohalic acid, for examplehydrochloric acid, which is used in dilute or concentrated aqueous form,or by treatment with an organic silyl halide, such astrimethyliodosilane or trimethylbromosilane, and, if necessary,subsequent hydrolysis. The reaction is preferably carried out atelevated temperature, for example by keeping the reaction mixture underreflux, and optionally, using an organic diluent, in a closed vesseland/or in an inert gas atmosphere. The type and manner of thereplacement of the protecting group R₆ is dependent, for example, uponthe substituent R which is contained in the compound of formula II andmust be retained when the compound II is converted into a compound offormula I. The said conversion may be carried out, for example, asdescribed in the Preparation Examples.

Amino-protecting groups R₈ in compounds of formula II can be removed byknown processes which are selected according to the type ofamino-protecting group, for example by solvolytic or hydrogenolyticprocesses, for example hydrolysis in the presence of an acid or base,acidolysis, for example treatment with trifluoroacetic acid, treatmentwith hydrazine, or hydrogenolysis in the presence of a metalhydrogenation catalyst, or by any other suitable process.

Depending upon the groups involved, the exchange and the conversion canbe carried out in succession or simultaneously in accordance withmethods known per se.

Preferably, all the protecting groups, hydroxy-protecting groups R₆ andR₁₀ and amino-protecting groups R₈ are replaced by hydrogen in a singlestep by treatment with a tri-lower alkylsily halide, such astrimethylbromosilane, or with an acid, preferably a hydrohalic acid,especially hydrochloric acid, under hydrolytic conditions.

The starting materials of formula II can be prepared in various ways,for example by

a) introducing into a compound of formula III ##STR4## wherein R₁, R₁ ',R₂ ' and R₃ are hydrogen, R₆ is a defined above and R₁₀ is hydrogen orprotected hydroxy, the group R₄ and, if desired, a radical R₅ other thanhydrogen, or

b) reacting a compound of formula IV ##STR5## wherein R₁, R₁ ', R₂ ° andR₃ are hydrogen, X is a reactive esterified hydroxy group and R₁₀ ishydrogen or protected hydroxy, or a salt thereof, with a compound offormula ##STR6## wherein R₄ and R₈ are defined above, or

c) condensing a compound of formula VI ##STR7## wherein R₁₁ is a groupR₆ or --Si(R₇)₃, R₁₂ is a radical R protected to a hydroxy group whichmay be present by a group --Si(R₇)₃, and the radicals R₇ are identicalor different aliphatic hydrocarbon radicals, for example lower alkyl,especially methyl and/or tert-butyl, with a compound of formula VII##STR8## wherein R₁, R₁ ', R₂ ' and R₃ are hydrogen, X₁ is reactiveesterified hydroxy and X₂ is hydrogen, or X₁ and X₂ together are epoxy,and R₈ is a group R₅ or an amino-protecting group, or

d) reacting a compound of formula VIII ##STR9## wherein R₁, R₁ ', R₂ 'and R₃ are hydrogen, R₉ is hydrogen or a group R₆ and R₁₀ is hydrogen orprotected hydroxy, with a silylating agent and reacting the resultingsilyl-activated compound of formula IX ##STR10## wherein R₈ is a groupR₅ other than hydrogen or is a group of the formula --Si(R₇)₃, R₁₁ is agroup R₆ or a group --Si(R₇)₃ and R₁₀ is hydrogen or a group of theformula --OSi(R₇)₃, and the radicals R₇ are identical or differentaliphatic hydrocarbon radicals, for example lower alkyl, especiallymethyl and/or tert-butyl, with a reactive ester of an aliphatic,cycloaliphatic, cycloaliphatic-aliphatic or araliphatic alcohol, with analiphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic orheteroarylaliphatic hydrocarbon having in the α,β-position an optionaladditional double bond, with an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, araliphatic or heteroarylaliphatic aldehyde orketon, or with an aliphatic epoxide, or

e) for the preparation of a compound of formula II wherein R₂ ishydroxy, reacting a compound of formula X ##STR11## in the form of ametal salt of formula XI ##STR12## wherein R₁₁ is a group R₆ or--Si(R₇)₃ and R₁₂ is a radical R protected at a hydroxy group which maybe present by a group --Si(R₇)₃, in which the radicals R₇ are identicalor different aliphatic hydrocarbon radicals, for example lower alkyl,especially methyl and/or tert-butyl, and M⁺ is an alkali metal cation,alkaline earth metal cation or transition metal cation, with an aldehydeof formula XII ##STR13##

If desired, a radical R₅ other than hydrogen may in each case beintroduced into a compound of formula II, wherein R₅ is hydrogen, thatis obtained initially.

The introduction of the radical R₄ and, optionally, R₅ according toprocess variant a) is effected in customary manner, for example byreaction with a compound of formula X-R₂ (IIIa) wherein X is a reactiveesterfied hydroxy group, especially in the presence of a basiccondensation agent, such as a tertiary organic base, for example atri-lower alkylamine, for example triethylamine, triisopropylamine ortert-butyl(dimethyl)amine, or pyridyl, or of a quaternary organicammonium base, for example benzyl(trimethyl)ammonium hydroxide. Suitablereactive hydroxy groups are preferably hydroxy groups esterfied by amineral acid, such as halogen, especially bromine, chlorine or iodine,or groups of the formula R₄ --O--SO₄ --O--.

The radical R₄ can, however, also be introduced by reaction with acompound of formula O═R₄ " (IIIb) wherein R₄ ' is a divalent araliphaticor heteroarylaliphatic radical the free valencies of which emanate fromthe same carbon atoms, under reductive conditions, especially in thepresence of an alkali metal borohydride, for example sodiumcyanoborohydride, preferably in a lower alkanol, such as ethanol,methanol or butanol.

The condensation of the compound of formula IV with amines of formula Vaccording to process variant b) is effected in a manner analogous tothat described above for the reaction of compounds of formula III.

In compounds of formula VII according to process variant c), reactiveesterified hydroxy is preferably halogen, such as bromine, iodine orchlorine, or sulfonyloxy, such as lower alkanesulfonyloxy, for examplemethanesulfonyloxy, or unsubstituted or substituted benzenesulfonyloxy,for example benzene-, p-toluene- or p-bromobenzene-sulfonyloxy.Amino-protecting groups are especially silyl groups, for example of theformula --Si(R₇)₃, such as tri-lower alkylsilyl, for exampletrimethylsilyl. The reaction of compounds of formula VI and reactiveesters VII can be carried out in a manner known per se, preferably underthe conditions of the Arbusow reaction, advantageously in a temperaturerange of from approximately 60° C. to approximately 180° C., for exampleat from approximately 120° C. to approximately 160° C. The reaction ofcompounds of formula VI with epoxides (VII; X₁ +X₂ =epoxy), on the otherhand, is preferably carried out in the presence of a mild Lewis acid,especially zinc chloride, advantageously in an aprotic solvent.

Silylating agents that can be used in accordance with process variant d)are especially tri-lower alkylhalosilanes of formula (R₇)₃ Si-Hal(VIIIa) wherein R₇ is lower alkyl and Hal is halogen, such as chlorine,bromine or iodine, such as trimethylchlorosilane ortrimethylbromosilane, or hexa-lower alkyldisilazanes of formula (R₇)₃Si--NH--Si(R₇)₃ (VIIIb) wherein R₇ is lower alkyl, such ashexamethyldisilazane. The silyl-activated intermediate is preferably acompound of formula IXa ##STR14##

The reaction of the intermediate of formula IX or IXa with the componentintroducing the radical R is preferably carried out in the presence of abasic condensation agent, such as a tertiary organic base, for example atri-lower alkylamine, for example triethylamine, triisopropylamine ortert-butyl(dimethyl)amine, or pyridine, or in the presence of aquaternary organic ammonium base, for example benzyl(trimethyl)ammoniumhydroxide.

In starting materials of formula X for process variant e), transitionmetal cations are, for example, lithium, sodium or potassium cations orgroups of the formula --Mg--Hal or --Zn--Hal wherein Hal is chlorine,bromine or iodine. The condensation of compounds of formulae XI and XIIis effected in the manner customary for such organometal reactions.

The introduction of a radical R₅ other than hydrogen is effected incustomary manner, especially as indicated under process variant a).

Resulting salts can be converted into the free compounds in a mannerknown per se, for example by treatment with a base, such as an alkalimetal hydroxide, a metal carbonate or hydrogen carbonate or ammonia, oranother salt-forming base mentioned at the beginning, or with an acid,such as a mineral acid, for example hydrochloric acid, or anothersalt-forming acid mentioned at the beginning.

Resulting salts can be converted into different salts in a manner knownper se; acid addition salts, for example, by treatment with a suitablemetal salt, such as a sodium, barium or silver salt, of a different acidin a suitable solvent in which an inorganic salt that forms is insolubleand is therefore eliminated from the reaction equilibrium; and basesalts by freeing the free acid and forming a salt again.

The compounds of formula I, including their salts, may also be obtainedin the form of hydrates or include the solvent used for crystallisation.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, hereinbefore and hereinafter anyreference to the free compounds or their salts should be understood asincluding the corresponding salts or free compounds, as appropriate andexpedient.

Resulting diastereoisomeric mixtures and mixtures of racemates can beseparated into the pure diastereoisomers or racemates in known manner onthe basis of the physico-chemical difference between the constituents,for example by means of chromatography and/or fractionalcrystallisation.

Furthermore, resulting racemates can be separated into the opticalantipodes by known methods, for example by recrystallisation from anoptically active solvent, with the aid of microorganisms, or by reactionof the resulting diastereoisomeric mixture of racemate with an opticallyactive auxiliary compound, for example, according to the acid, basic orfunctionally modifiable groups contained in compounds of formula I, withan optically active acid, base or an optically active alcohol, to formmixtures of diastereoisomeric salts or functional derivatives, such asesters, and separation thereof into the diastereoisomers from which thedesired enantiomer can be freed in the customary manner. Suitable basis,acids and alcohol are, for example, optically active alkaloid bases,such as strychnine, cinchonine or brucine, or D- orL-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similarsynthetically obtainable bases, optically active carboxylic or sulfonicacids, such as quinic acid or D- or L-tartaric acid, D- orL-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid orD- or L-camphorsulfonic acid, and optically active alcohols, such asborneol or D- or L-(1-phenyl)ethanol.

The invention relates also to those forms of the process in which acompound obtainable as intermediate at any stage of the process is usedas starting material and the remaining steps are carried out, or inwhich a starting materials is used in the form of a salt or, especially,is formed under the reaction conditions.

The invention relates also to the novel starting materials developedspecifically for the preparation of the compounds according to theinvention, especially to those starting materials resulting in thecompounds of formula I that were described at the beginning as beingpreferred, to processes for the preparation thereof and to their use asintermediates.

Compounds of formula I wherein R₄ and R₅ are hydrogen, which are alsoused as starting materials for process variant a), can be prepared, forexample, by reacting a compound of formula XIII protected at the hydroxygroup which may be present ##STR15## wherein R₁, R₁ ', R₂, R₂ ' and R₃are as defined above, with a tri-lower alkylhalosilane, such astrimethylchlorosilane, or with a hexa-lower alkyldisilazane, for examplehexamethyldisilazane, and condensing the resulting silyl-activatedcompound of formula XIV ##STR16## wherein R₀ is a tri-lower alkylsilygroup, such as trimethylsily, and Z₀ is N,N-di(tri-loweralkylsily)amino, with a corresponding aliphatic,cycloaliphatic-aliphatic or araliphatic halide of formula R--Hal (XV;Hal=halogen) or an aliphatic, cycloaliphatic-aliphatic or araliphaticaldehyde of formula R'--CH═O (XVI) wherein R' is a radical R reduced bya terminal CH₂ group, to form the corresponding compound of formula XVII##STR17## wherein R is an aliphatic, cycloaliphatic-aliphatic oraraliphatic radical or a group of the formula R--CH(OH)--, or reactingthe compound of formula XIV with an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic ketone of formula R"--C(═O)--R"'(XVIII), wherein R" is an aliphatic, cycloaliphatic or aromatic radicaland R"' is an aliphatic radical, to form the corresponding compound offormula V wherein R is a radical of the formula R"--C(R"')(OH)--, orwith a corresponding aliphatic, cycloaliphatic-aliphatic or araliphaticepoxide or a corresponding aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic compound having at least oneadditional olefinic double bond, and in each case working up the primaryproduct, for example of formula XVII, by hydrolysis.

Compounds of formula I wherein R₁ and R₁ ' are hydrogen, R₂ is anaromatic radical, R₂ ' is hydroxy and R₃, R₄ and R₅ are hydrogen, whichare also used as starting materials for process variant a), can beprepared especially by reacting compounds of formulae XIX and XX##STR18## in an araliphatic solvent, such as toluene, to form thecorresponding compound of formula XXI ##STR19## and converting thelatter by reaction first with a haloformic acid lower alkyl ester, suchas chloroformic acid ethyl ester, in the presence of a tri-loweralkylamine, such as triethylamine, and then with an orthoacetic acidtri-lower alkyl ester, such as orthacetic acid triethyl ester, in thepresence of a Lewis acid, such as boron trifluroide, into a compound offormula XXII ##STR20##

The compound of formula XXII is then reacted in the presence of the 1:1complex of copper(I) bromide and dimethyl sulfide with a compound offormula R₂ --M (XXIII), wherein M is a metal radical, especially ahalomagnesium group, to form the corresponding compound of formula XXIV##STR21##

In a one-pot reaction the P-protecting groups (lower alkyl radicals) canthen be removed by treatment with trimethylchlorosilane indichloromethane/ethanol and the group R can be introduced by reactionwith a compound of formula XV, XVI or XVIII, with an aliphatic,cycloaliphatic-aliphatic or araliphatic epoxide or a correspondingaliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphaticunsaturated compound, as described for the reaction thereof withcompounds of formula XIV. The resulting compound of formula XXV##STR22## is then reacted in an acetonitrile/tert-butanol/water mixturein the presence of silver nitrate and osmium tetroxide with a reagentobtained by reaction of tert-butylurethane with tert-butoxy chloride ina lower alkanol in the presence of sodium hyroxide. The primary productso obtained is then converted by means of trimethylbromosilane indichloromethane and treatment with aqueous methanol and then withpropylene oxide into the desired compound of formula XXVI ##STR23##wherein R₀ is a silyl group and Z₀ ' is tert-butoxycarbonyl. Treatmentwith aqueous methanol and then with propylene oxide yields the desiredcompound of formula I.

The novel compounds of formula I can be used, for example, in the formof pharmaceutical composition that comprise a therapeutically effectiveamount of the active ingredient, optionally together with inorganic ororganic, solid or liquid pharmaceutically acceptable carriers that aresuitable for enteral, for example oral, or parenteral administration.

Pharmaceutical compositions that comprise known GABA_(B) -antagonists,for example known compounds of formula I, are intended especially asanti-epileptics.

The pharmaceutical compositions according to the invention arepharmaceutical compositions in unit dose from that comprise atherapeutically effective amount of the active ingredient on its own ortogether with a pharmaceutically acceptable carrier, especiallyinorganic or organic, solid or liquid pharmaceutically acceptablecarriers, so that they are suitable for enteral, such as oral, and alsorectal, and parenteral administration to warm-blooded animals.

The pharmaceutical compositions, such as anti-epileptics, providedaccording to the invention comprise, for example, from approximately 10%to approximately 80%, preferably from approximately 20% to approximately60%, active ingredient. Pharmaceutical compositions according to theinvention for enteral or parenteral administration are, for example,pharmaceutical compositions in unit dose form, such as dragees, tablets,capsules or suppositories, and also injection or infusion solutions,preferably in ampoules. The compositions are prepared in a manner knownper se, for example by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes. For example,pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture and, if desired or necessary, processingthe mixture or granules, after the addition of suitable excipients, toform tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tri-calcium, phosphate or calciumhydrogen phosphate, and binders, such as starch pastes for example,corn, wheat, rice or potato starch, gelatin, tragacanth, methylcelluloseand/or polyvinylpyrrolidone, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, agar, alginic acid or a salt thereof, such assodium alginate. Excipients are especially flow conditioners andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol. Dragee cores are provided with suitable, optionally enteric,coatings, there being used, inter alia, concentrated sugar solutionswhich may comprise gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or dragee coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Other orally administrable pharmaceutical compositions are dry-filledcapsules consisting of gelatin, and also soft sealed capsules consistingof gelatin and a plasticiser, such as glycerol or sorbitol. Thedry-filled capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and, if desired, stabilisers. In soft capsules, the activeingredient is preferably dissolved or suspended in suitable liquids,such as fatty oils, paraffin oil or liquid polyethylene glycol, to whichstabilisers may also be added.

Suitable rectally administrable pharmaceutical compositions are, forexample, suppositories that consist of a combination of the activeingredient with a suppository base. Suitable suppository bases are, forexample, natural or synthethic triglycerides, paraffin hydrocarbons,polyethylene glycol or higher alkanols. There may also be used gelatinrectal capsules, which contain a combination of the active ingredientwith a base material. Suitable base materials are, for example, liquidtriglycerides, polyethylene glycols of paraffin hydrocarbons.

For parenteral administration there are suitable, especially, aqueoussolutions of an active ingredient in water-soluble form, for example inthe form of a water-soluble salt, and also suspensions of the activeingredient, such as corresponding oily injection suspensions, therebeing used suitable lipophilic solvents or vehicles, such as fatty oils,for example sesame oil, or synthetic fatty acid esters, for exampleethyl oleate or triglycerides, or aqueous injection suspensions thatcomprise viscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran, and, if desired, alsostabilisers.

The pharmaceutical compositions can be sterilised, if desired, comprisefurther pharmacologically active substances and/or excipients, forexample preservatives, stabilisers, wetting agents and/or emulsifiers,solubilisers, salts for regulating the osmotic pressure and/or buffers.

The dosage can depend upon various factors, such as the mode ofadministration, the species, age and/or individual condition. The dailydoses are, in the case of oral administration, from approximately 5 toapproximately 60 mg/kg, especially from 10 to approximately 40 mg/kg,and in the case of warm-blooded animals having a body weight ofapproximately 40 kg, they are preferably from approximately 200 mg toapproximately 2400 mg, especially from approximately 400 toapproximately 1600 mg, which is advantageously divided into from 2 to 6,for example 3 or 4, single doses.

The following Examples illustrate the invention; temperature are givenin degrees Celsius and pressures in mbar.

PREPARATION EXAMPLE 1

A solution of 0.36 g of lithium hydroxide monohydrate in 7 ml of wateris added to a solution of 1.61 g of3-(p-chlorobenzylamino)propyl(diethoxymethylphosphinic acid ethyl esterin 3 ml of ethanol, and the mixture is heated at 60° for 24 hours. Themixture is then cooled to room temperature and the solvent is removedunder reduced pressure. The evaporation residue is taken up in water andneutralised with phosphoric acid. A white precipitate forms and isfiltered off, and the filtrate is concentrated to dryness byevaporation. The white residue is dried under reduced pressure andcrystallised from toluene/diethyl ether. Filtration with suction anddrying yield 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinicacid having a melting point of 177°-179°.

The starting material can be prepared, for example, as follows:

1.41 g of p-chlorobenzaldehyde are added to a solution of 2.53 g of3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester in 10 ml ofanhydrous methanol, and the resulting clear solution is stirred at roomtemperature for 30 minutes. There are then added first 0.6 g of glacialacetic acid and then, dropwised, 0.21 g of sodium cyanoborohydride insolution in 5 ml of methanol. An exothermic reaction begins. The mixtureis stirred at 20° for 3 hours and adjusted at pH 8, and the solvent isremoved. The residue is dissolved in dichlormethane and washed withwater. The organic phase is separated off, dried over sodium sulfate andconcentrated to dryness by evaporation. The oil that remains is purifiedby chomatography on silica gel, yielding3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl esterin the form of a yellowish oil.

PREPARATION EXAMPLE 2

A solution of 1.80 g of(2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acidethyl ester in 30 ml of semi-concentrated hydrochloric acid is heatedunder reflux, a whitish suspension forming after 30 minutes. The mixtureis heated under reflux for a further 20 hours and cooled to 0°, and thesolid portion is filtered off, washed with water and dried under reducedpressure at 60°. Recrystallisation from aqueous methanol and dryingyield 3-(p-chlorobenzylamino)-2-(2S)-hydroxypropyl(benzyl)phosphinicacid hydrochloride having a melting point of 211.5°-212°.

The starting material can be prepared as follows:

A solution of diethoxymethylphosphinic acid ethyl ester is added withina period of 90 minutes, under argon, to a suspension of 13.2 g of 99%sodium hydride in 500 ml of tetrahydrofuran, the temperature beingmaintained at 20°. The reaction is exothermic and is accomplished by theevolution of gas. The mixture is then stirred for 90 minutes, and 85.5 gof benzyl bromide are then added within a period of 20 minutes. Themixture is then stirred at room temperature for 24 hours and cooled to0°, and 100 ml of water are added carefully. The organic solvents areremoved under reduced pressure and the residue is partitioned betweenwater and dichloromethane. The organic phase is separated off, washedwith water, dried over sodium sulfate and concentrated by evaporation.Distillation of the residue under reduced pressure yieldsdiethoxymethyl(benzyl)phosphinic acid ethyl ester having a boiling pointof 103°-110° (3×10⁻⁴ bar).

A suspension of 128 g of diethoxymethyl(benzyl)phosphinic acid ethylester in 400 ml of hydrochloric acid is heated under reflux for 20hours, cooled to room temperature, washed with diethyl ether/hexane(1:1) and concentrated to dryness by evaporation. The residue is takenup in dichloromethane, dried over sodium sulfate and again concentratedby evaporation. The viscous benzylphosphinic acid that remains is thendried under a high vacuum. 13.34 g of benzylphosphinic acid aredissolved in 150 ml of dichloromethane, the solution is cooled to 5°,and 8.64 g of triethylamine are added dropwise. An exothermic reactiontakes place. The mixture is cooled to 5° again, and 9.3 g ofchloroformic acid ethyl ester are added dropwise within a period of 30minutes. A precipitate forms in an exothermic reaction with theevolution of gas. The mixture is allowed to warm to room temperature andis then stirred at room temperature for 3 hours, taken up indichloromethane and washed with water, and the organic solvent isremoved. The crude product is distilled under a high vacuum, yieldingbenzylphosphinic acid ethyl ester having a boiling point of 96°100°(5×10⁻⁶ bar).

26.7 g of benzylphosphinic acid ethyl ester and 16.0 g of triethylamineare dissolved in 250 ml of tetrahydrofuran, 17.33 g oftrimethylchlorosilane are added, and the mixture is stirred overnight atroom temperature. The white precipitate that has formed is filtered offunder argon and the filtrate is concentrated by evaporation underreduced pressure. 14.71 g of (R)-epichlorohydrin and 2.5 g of zincchloride are added to the residue. When the exothermic reaction hassubsided, the mixture is heated under reflux for 7.5 hours at 60°. Themixture is allowed to cool to room temperature, diluted withdichloromethane and washed with water. The organic phase is separatedoff, dried over sodium sulfate and concentrated by evaporation. The oilyresidue is taken up with 1% methanolic acetic acid, left to stand atroom temperature for 20 hours and concentrated by evaporation. Theresidue is purified by chromatography on silica gel, yielding(2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinic acid ethyl ester; ¹H--NMR spectrum (in CDCl₃): δ=7.3 (5H,m); 2.19-3.92 (3H,m); 3.6-3.42(2H,m); 3.21 (2H,d;J=15.0 Hz); 2.16-1.81 (2H,m); 1.30 (3H,t); ³¹ P--NMRspectrum (in CDCl₃); δ=52.1.

A mixture of 2.76 g of (2R)-3-chloro-2-hydroxypropyl(benzyl)phosphinicacid ethyl ester, 3.54 g of p-chlorobenzylamine, 3.25 g ofN-ethyl-N,N-diisopropylamine and 20 ml of ethanol is heated under refluxfor 48 hours. Removal of the solvent and chromatography yield(2S)-3-(p-chlorobenzylamino)-2-hydroxypropyl(benzyl)phosphinic acidethyl ester; ¹ H--NMR spectrum (in CDCl₃): δ=7.4-7.17 (9H,m); 4.14-3.83(3H,m); 3.71 (2H,ABq); 3.20 (2H,d); 2.6-2.5 (2H,m); 1.96-1.62 (2H,m);1.25 (3H,t); ³¹ P--NMR spectrum (in CDCl₃); δ=53.9; 52.7.

PREPARATION EXAMPLE 3

A solution of 1.86 g of 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinicacid ethyl ester in 30 ml of semi-concentrated hydrochloric acid isheated under reflux overnight, a clear solution forming after only 10minutes. The solution is then cooled to 0°, whereupon a whiteprecipitate forms. The precipitate is filtered off, washed with waterand dried under reduced pressure at 60°. Recrystallisation from waterand drying yield 3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acidhydrochloride having a melting pint of 212°-214°.

The starting material can be prepared as follows:

24 g of a 55% suspension of sodium hydride in mineral oil are washedunder argon with hexane and then taken up in 100 ml of tetrahydrofuran.The mixture is cooled to 0° and a solution of 104.4 g ofdiethoxymethylphosphinic acid ethyl ester in 100 ml of tetrahydrofuranis added dropwise under argon, the temperature being maintained at 20°.The reaction is exothermic and is accompanied by the evolution of gas.The mixture is then stirred for 90 minutes and then 209.7 g of n-butylbromide are added at 20°. The mixture is then stirred for 2.5 hours atroom temperature and cooled to 0°, and 100 ml of water are addedcarefully. The organic solvents are removed under reduced pressure, andthe residue is partitioned between water and dichloromethane. Theorganic phase is separated off, washed with water, dried over sodiumsulfate and concentrated by evaporation. Distillation of the residueunder reduced pressure yields diethoxymethyl(n-butyl)phosphinic acidethyl ester having a boiling pint of 71.5°-74° (10⁻⁶ bar).

A solution of 109 g of diethoxymethyl(n-butyl)phosphinic acid ethylester in 160 ml of 4N hydrochloric acid is heated under reflux for 24hours, cooled to room temperature, washed with diethyl ether andconcentrated to dryness by evaporation. The residue is subjected toazeotropic distillation with ethanol and concentrated by evaporationagain. The n-butyl-phosphinic acid that remains is dried under a highvacuum at 50° for 20 hours, yielding an oil; ¹ H--NMR spectrum (inCDCl₃); δ=11.13 (1H,s); 7.11 (1H,dt; J=52.0 and 0.2 Hz); 1.77 (2H,m);1.58 (2H,m); 0.3 (3H,t).

51 g of n-butylphosphinic acid are dissolved in 200 ml ofdichloromethane, the solution is cooled to 10°, and 42.3 g oftriethylamine are added dropwise. An exothermic reaction takes place.The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethylester are added dropwise within a period of 75 minutes. A precipitateforms in an exothermic reaction with the evolution of gas. A further 200ml of dichloromethane are then added and the mixture is allowed to warmto room temperature and is then stirred for 2 hours at room temperature,washed with water and dried over sodium sulfate, and the organic solventis removed. The crude product is distilled under a high vacuum, yieldingn-butylphosphinc acid ethyl ester having a boiling point of 95° (5×10⁻⁵bar).

15.0 g of n-butylphosphinic acid ethyl ester and 5.3 g of acrylonitrileare dissolved under argon in 25 ml of ethanol. The solution is cooled to10°, and a solution of 1.15 g of sodium in 50 ml of ethanol is addeddropwise, whereupon the exothermic reaction takes place. The mixture isthen heated under reflux for one hour and cooled to room temperature,and 3.3 g of glacial acetic acid are added. The solvent is removed andthe residue is taken up in dichloromethane. The resulting solution iswashed with water, dried over sodium sulfate and concentrated byevaporation. The oil that remains is distilled, yielding2-cyanoethyl(n-butyl)phosphinic acid ethyl ester having a boiling pointof 120° (10⁻¹ bar).

16.46 g of 2-cyanoethyl(n-butyl)phosphinic acid ethyl ester aredissolved in 165 ml of ethanol, the solution is mixed with 16.5 g ofammonia and 3.0 g of Raney nickel, and the mixture is hydrogenated for 2hours at 70°-75° under an initial pressure of 100 bar. The mixture isallowed to cool to room temperature, the catalyst is filtered off, thesolvent is removed and the residue is distilled, yielding3-aminopropyl(n-butyl)phosphinic acid ethyl ester having a boiling pointof 100° (10⁻⁵ bar).

4.14 g of 3-aminopropyl(n-butyl)phosphinic acid ethyl ester are mixedwith 2.51 g of p-chlorobenzaldehyde, and first 1.2 g of glacial aceticacid and then a solution of 0.42 g of sodium cyanoborohydride in 5 ml ofmethanol are added, whereupon an exothermic reaction takes place. Themixture is then stirred at room temperature for 2.5 hours and adjustedto pH 8, and the volatile constituents are removed under reducedpressure. The residue is dissolved in dichloromethane, washed withwater, dried over sodium sulfate and concentrated by evaporation. Theresidue is purified by chromatography on silic gel, yielding3-(p-chlorobenzylamino)propyl(n-butyl)phosphinic acid ethyl ester; ¹H--NMR spectrum (in CDCl₃): δ=7.30-7.32 (4H,m); 4.02 (2H,q); 3.74(2H,s); 2.67 (2H,t); 2.5-2.2 (1H,S); 1.79-1.64 (6H,m); 1.53 (2H,m); 1.42(2H,m); 1.31 (3H,t); 0.81 (3H,t); ³¹ P--NMR spectrum (in CDCl₃);δ=58.16.

PREPARATION EXAMPLE 4

In a manner analogous to that described in Preparation Example 1,3-(p-chlorobenzylamino)propyl(cyclohexylmethyl)phosphinic acid having amelting point of 218°-219° can be prepared starting from3-aminopropyl(cyclohexylmethyl)phosphinic acid ethyl ester andp-chlorobenzaldehyde.

PREPARATION EXAMPLE 5

In a manner analogous to that described in Preparation Example 2,3-(p-chlorobenzylamino)-2-(2R)-hydroxypropyl(benzyl)phosphinic acidhaving a melting point of 218°222° can be prepared starting frombenzylphosphinic acid ethyl ester, (S)-epichlorohydrin andp-chlorobenzaldehyde.

PREPARATION EXAMPLE 6

In a manner analogous to that described in Preparation Example 1,3-(3,4-dichlorobenzylamino)propyl(diethoxymethyl)phosphinic acid havinga melting point of 175°-176° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester and3,4-dichlorobenzaldehyde.

PREPARATION EXAMPLE 7

In a manner analogous to that described in Preparation Example 1,3-[1-(p-chlorophenyl)ethylamino]propyl(diethoxymethyl)phosphinic acid,hygroscopic crystals, ³¹ P--NMR (CD₃ OD); δ=47.1 ppm, can be preparedstarting from 3-aminopropyl(diethyoxymethyl)phosphinic acid ethyl esterand p-chloroacetophenone.

PREPARATION EXAMPLE 8

In a manner analogous to that described in Preparation Example 1,3-(naphth-1-ylmethylamino)propyl(diethoxymethyl)phosphinic acid having amelting point of 222°-225° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester and1-formylnaphthalene.

PREPARATION EXAMPLE 9

In a manner analogous to that described in Preparation Example 3,3-(3,4-dichlorobenzylamino)propyl(diethoxymethyl)phosphinic acidhydrochloride having a melting point of 115°-226° can be preparedstarting from 3-aminopropyl(diethoxymethyl)phosphinic acid ethyl esterand 3,4-dichlorobenzaldehyde.

PREPARATION EXAMPLE 10

In a manner analogous to that described in Preparation Example 3,3-(pyrid-2-ylmethylamino)-2(S)-hydroxypropyl(benzyl)phosphinic acidhydrochloride, [α]₂₀ ^(D) =10.2±0.2 (c=1% in CH₃ OH), can be preparedstarting from 3-chloro-2(R)-hydroxypropyl(benzyl)phosphinic acid ethylester and 2-aminomethylpyridine.

PREPARATION EXAMPLE 11

In a manner analogous to that described in Preparation Example 2,3-(p-chlorobenzylamino)-2(S)-hydroxypropyl(cyclohexylmethyl)phosphinicacid hydrochloride having a melting point of 206°-210° can be preparedstarting from 3-chloro-2(R)-hydroxypropyl(cyclohexylmethyl)phosphinicacid ethyl ester and p-chlorobenzylamine.

PREPARATION EXAMPLE 12

In a manner analogous to that described in Preparation Example 2,3-(3,4-dichlorobenzylaminoyl)-2(S)-hydroxypropyl(benzyl)phosphinic acidhydrochloride having a melting point of 186°-187° can be preparedstarting from 3-chloro-2(R)-hydroxypropyl(benzyl)phosphinic acid ethylester and 3,4-dichlorobenzylamine.

PREPARATION EXAMPLE 13

In a manner analogous to that described in Preparation Example 1,3-(p-fluorobenzylamino)propyl(diethoxymethyl)phosphinic acid having amelting point of 128°-129° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester andp-fluorobenzaldehyde.

PREPARATION EXAMPLE 14

In a manner analogous to that described in Preparation Example 1,3-(m-chloro-3-trifluoromethylbenzylamino)propyl(diethoxymethyl)phosphinicacid having a melting point of 138°-139° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester and4-chloro-3-trifluoromethylbenzaldehyde.

PREPARATION EXAMPLE 15

In a manner analogous to that described in Preparation Example 1,3-(m-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid having amelting point of 158°-160° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester andm-chlorobenzaldehyde.

PREPARATION EXAMPLE 16

In a manner analogous to that described in Preparation Example 2,3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(cyclohexylmethyl)phosphinicacid hydrochloride having a melting point of 193°-196° can be preparedstarting from 3-chloro-2(R)-hydroxypropyl(cyclohexylmethyl)phosphinicacid ethyl ester and 3,4-dichlorobenzylamine.

PREPARATION EXAMPLE 17

In a manner analogous to that described in Preparation Example 1,3-[1-(3,4-dichlorophenyl)ethylamino]propyl(diethoxymethyl)phosphinicacid having a melting point of 85°-90° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester and3,4-dichloroacetophenone.

PREPARATION EXAMPLE 18

In a manner analogous to that described in Preparation Example 2,3-[1-(p-chlorophenyl)aminoethyl]-2(S)-hydroxypropyl(benzyl)phosphinicacid hydrochloride having a melting point of 93°-95° can be preparedstarting from 3-chloro-2(R)-hydroxypropyl(benzyl)phosphinic acid ethylester and 1-(p-chlorophenyl)ethylamine.

PREPARATION EXAMPLE 19

In a manner analogous to that described in Preparation Example 1,3-(p-iodobenzylamino)propyl(diethoxymethyl)phosphinic acid having amelting point of 108°-110° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester andp-iodobenzaldehyde.

PREPARATION EXAMPLE 20

In a manner analogous to that described in Preparation Example 1,3-(2,4-dichlorobenzylamino)propyl(diethoxymethyl)phosphinic acid havinga melting point of 173°-175° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester and2,4-dichlorobenzaldehyde.

PREPARATION EXAMPLE 21

In a manner analogous to that described in Preparation Example 1,3-(o-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid having amelting pint of 162°-163° can be prepared starting from3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester ando-chlorobenzaldehyde.

PREPARATION EXAMPLE 22

In a manner analogous to that described in Preparation Example 1,3-(3,4-dichlorobenzylamino)propyl(cyclopropylmethyl)phosphinic acidhaving a melting pint of 214°-215° can be prepared starting from3-aminopropyl(cyclopropylmethyl)phosphinic acid ethyl ester and3,4-dichlorobenzaldehyde.

PREPARATION EXAMPLE 23

0.38 g of trimethylbromosilane is added to a solution of 0.41 g of3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinic acid ethylester, the mixture is stirred at room temperature for 24 hours, and thevolatile constituents are removed under reduced pressure. The oil thatremains is taken up in 99% methanol, stirred for 30 minutes at roomtemperature and again concentrated by evaporation under reducedpressure. Recrystallisation of the solid yellowish residue yields3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinic acidhydrochloride having a melting pint of 212°-213°; ¹ H--NMR spectrum (inCD₃ OD): δ=7.5 (4H,m), 4.21 (2H,s), 4.03 (1H,ABq), 3.84 (2H,t,d), 3.17(2H,t), 2.30-1.83 (8H,m); ³¹ P--NMR spectrum (in CD₃ OD): δ=49.4.

PREPARATION EXAMPLE 24

0.43 g of lithium hydroxide monohydrate in 6 ml of water is added to asolution of 2.0 g of3-[N-(p-chlorobenzyl-N-methylamino]propyl(diethoxymethyl)phosphinic acidethyl ester in 5.5 ml of ethanol, and the mixture is heated at 60° for25 hours. The mixture is then cooled to room temperature and the solventis removed under reduced pressure. The evaporation residue is taken upin water and neutralised with phosphoric acid. The suspension formed isconcentrated to dryness by evaporation, and the residue is taken up inhot methanol, filtered and concentrated by evaporation again.Crystallisation of the residue from propanol yields3-[N-(p-chlorobenzyl)-N-methylamino](diethoxymethyl)phosphinic acidhaving a melting point of 170°-171.5°.

The starting material can be prepared, for example, as follows:

2.5 g of 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acidethyl ester are dissolved in 10 ml of methanol, 0.36 g (0.53 ml) of a35% aqueous formaldehyde solution is added, and the mixture is stirredat room temperature for one hour. 0.4 g of glacial acetic acid and 0.40g of sodium cyanoborohydride are added, and the mixture is stirred atroom temperature for 2 hours, concentrated by evaporation under reducedpressure, taken up in dichloromethane and washed with 5% aqueous sodiumhydrogen carbonate solution. The organic phase is separated off, driedover sodium sulfate and concentrated by evaporation under reducedpressure. The oily residue is purified by chromatography on silica gel,yielding 3-(p-chlorobenzylamino)propyl(tetrahydrofuran-2-yl)phosphinicacid ethyl ester in the form of a colourless oil.

PREPARATION EXAMPLE 25

In a manner analogous to that described in Preparation Example 23-(p-chlorobenzylamino)-2(S)-hydroxy-propyl(p-chlorobenzyl)phosphinicacid hydrochloride in m.p. 226°-228° can be manufactured.

PREPARATION EXAMPLE 26

In a manner analogous to that described in Preparation Example 23-(3,4-dichlorobenzylamino)-2(S)-hydroxy-propyl(p-chlorbenzyl)phosphinicacid hydrochloride can be manufactured.

PREPARATION EXAMPLE 27

In a manner analogous to that described in Preparation Example 23-(p-chlorobenzylamino)-2(S)-hydroxy-propyl(p-methylbenzyl)phosphinicacid hydrochloride of m.p. 209°-219° can be manufactured. Dissolution inethanol and treatment with propylenoxide yields.3-(p-chlorobenzylamino)-2(S)-hydroxy-propyl(p-methylbenzyl)phosphinicacid of m.p. 239.5°-241.

PREPARATION EXAMPLE 28

In a manner analogous to that described in Preparation Example 23-(3,4-dichlorobenzylamino)-2(S)-hydroxy-propyl(p-metrhylbenzyl)phosphinicacid hydrochloride can be manufactured. Dissolution in ethanol andtreatment with propylenoxide yields3-(3,4-dichlorobenzylamino)-2(S)-hydroxy-propyl(p-methylbenzyl)phosphinicacid of m.p. 222.5°-224°.

PREPARATION EXAMPLE 29

In a manner analogous to that described in Preparation Examples 1 to 24,the following may also be prepared:

3-(p-chlorobenzylamino)-2(S)-hydroxypropyl)diethoxymethyl)phosphinicacid;

3-[1-(p-chlorophenyl)ethylamino]-2(S)-hydroxypropyl(diethoxymethyl)phosphinicacid;

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(diethoxymethyl)phosphinicacid;

3-[1-(3,4-dichlorophenyl)ethylamino]-2(S)-hydroxypropyl(diethoxymethyl)phosphinicacid;

3-[N-(p-chlorobenzyl)-N-methyl-amino]-2(S)-hydroxy(benzyl)phosphinicacid;

3-(p-chlorobenzylamino)-2(S)-hydroxypropyl(p-methoxybenzyl)phosphinicacid;

3-(p-chlorobenzylamino)-2(S)-hydroxypropyl(3,4-dimethoxybenzyl)phosphinicacid;

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(3,4-dimethoxybenzyl)phosphinicacid;

3-[2-(p-chlorophenyl)prop-2-ylamino]propyl(diethoxymethyl)phosphinicacid;

3-[2-3,4-dichlorophenyl)prop-2-ylamino]propyl(diethoxymethyl)phosphinicacid;

3-[2-(p-chlorophenyl)prop-2-ylamino]-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-[2-(3,4-dichlorophenyl)prop-2-ylamino)-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(3,4,5-trihydroxycyclohexylmethyl)phosphinicacid;

3-(4-chloro-3-methoxy-benzylamino)propyl(diethoxymethyl)phosphinic acid;

3-(4-chloro-3-methoxy-benzylamino)-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-(3-chloro-4-methoxy-benzylamino)-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-(2-phenylethylamino)propyl(diethoxymethyl)phosphinic acid;

3-(2-phenylethylamino)-2(S)-hydroxypropyl(diethoxymethyl)phosphinicacid;

3-(p-chlorobenzylamino-2(S)-hydroxypropyl(4-methoxycyclohexylmethyl)phosphinicacid;

3-(3,4-dichloro-6-iodo-benzylamino)-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-(3,4-dichloro-6-iodo-benzylamino)propyl(diethoxymethyl)phosphinicacid;

3-(4-chloro-3-iodo-benzylamino)propyl(diethoxymethyl)phosphinic acid;

3-(3-chloro-4-iodo-benzylamino)propyl(diethoxymethyl)phosphinic acid;

3-(4-chloro-3-iodo-benzylamino)-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-(3-chloro-3-iodo-benzylamino)-2(S)-hydroxypropyl(benzyl)phosphinicacid;

3-Di(p-chlorobenzyl)aminopropyl(diethoxymethyl)phosphinic acid;

3-Di(3,4-dichlorobenzyl)amino-2(S)-hydroxypropyl(benzyl)phosphinic acid;

3-(3,4-dichlorobenzyl)amino-2(S)-hydroxypropyl(cyclohex-3-enylmethyl)phosphinicacid

3-[1-(3,4-dichlorophenyl)ethylamino]-2(S)-hydroxypropyl(cyclohex-3-enylmethyl)phosphinicacid;

3-(3,4-dichlorobenzyl(amino)-2(S)-hydroxypropyl(cis-4,5-dihydroxycyclohexylmethyl)phosphinicacid and

3-[1-(3,4-dichlorophenyl)ethylamino]-2(S)-hydroxypropyl(cis-4,5-dihydroxycyclohexylmethyl)phosphinicacid

and their pharmaceutically acceptable salts, for example theirhydrochlorides.

FORMULATION EXAMPLE 1

Tablets, each comprising 200 mg of3-aminopropyl(cyclohexylmethyl)phosphinic acid or a salt, for examplethe hydrochloride, thereof, can be prepared as follows:

    ______________________________________                                        Composition (10 000 tablets)                                                  ______________________________________                                        active ingredient      2000.0  g                                              lactose                500.0   g                                              potato starch          352.0   g                                              gelatin                8.0     g                                              talc                   60.0    g                                              magnesium stearate     10.0    g                                              silica (highly dispersed)                                                                            20.0    g                                              ethanol                q.s.                                                   ______________________________________                                    

The active ingredient is mixed with the lactose and 292 g of potatostarch, and the mixture is moistened with an ethanolic solution of thegelatin and granulated through a sieve. After drying, the remainingpotato starch, the magnesium stearate, the talc and the silica are mixedin and the mixture is compressed to form tablets which each weight 295.0mg and comprise 50.0 mg of active ingredient, and which may, if desired,be provided with dividing notches for finer adaptation of the dose.

FORMULATION EXAMPLE 2

Film-coated tablets, each comprising 400 mg of3-aminopropyl(cyclohexylmethyl)phosphinic acid or a salt, for examplethe hydrochloride, thereof, can be prepared as follows:

    ______________________________________                                        Composition (for 1000 coated tablets)                                         ______________________________________                                        active ingredient        400.0                                                                              g                                               lactose                  100.0                                                                              g                                               corn starch              70.0 g                                               talc                     8.5  g                                               calcium stearate         1.5  g                                               hydroxypropylmethylcellulose                                                                           2.36 g                                               shellac                  0.64 g                                               water                    q.s.                                                 methylene chloride       q.s.                                                 ______________________________________                                    

The active ingredient, the lactose and 40 g of the corn starch aremixed, and the mixture is moistened with a paste, prepared from 15 g ofthe corn starch and water (with heating), and granulated. The granulesare dried, the remaining corn starch, the talc and the calcium stearateare added and mixed with the granules. The mixture is compressed to formtablets, hich are coated with a solution of thehydroxypropylmethylcellulose and the shellac in methylene chloride;final weight of the film-coated tablet: 580 mg.

FORMULATION EXAMPLE 3

Gelatin dry-filled capsules, containing 500 mg of active ingredient, forexample 3-aminopropyl(cyclohexylmethyl)phosphinic acid or a salt, forexample the hydrochloride, thereof, can be prepared, for example, asfollows:

    ______________________________________                                        Composition (for 1000 capsules)                                               ______________________________________                                        active ingredient        500.0  g                                             lactose                  250.0  g                                             microcrystalline cellulose                                                                             30.0   g                                             sodium lauryl sulfate    2.0    g                                             magnesium stearate       8.0    g                                             ______________________________________                                    

The sodium lauryl sulfate is added to the lyophilised active ingredientthrough a sieve having a mesh size of 0.2 mm. The two components areintimately mixed. Then, first the lactose is added through a sievehaving a mesh size of 0.6 mm and then the microcrystalline cellulosethrough a sieve having a mesh size of 0.9 mm. The mixture is againintimately mixed for 10 minutes. Finally, the magnesium stearate isadded through a sieve having a mesh size of 0.8 mm. After further mixingfor 3 minutes, gelatin dry-fill capsules of a suitable size are eachfilled with 790 mg of the resulting formulation.

FORMULATION EXAMPLE 4

A 5% injection or infusion solution of3-aminopropyl(cyclohexylmethyl)phosphinic acid or of a salt, for examplethe hydrochloride, thereof can be prepared, for example, as follows:

    ______________________________________                                        Composition (for 1000 ro 400 ampoules)                                        ______________________________________                                        active ingredient     125.0    g                                              sodium chloride       22.5     g                                              phosphate buffer pH = 7.4                                                                           300.0    g                                              demineralized water   ad 2500.0                                                                              ml                                             ______________________________________                                    

The active ingredient and the sodium chloride are dissolved in 1000 mlof water and filtered through a micro-filter. The buffer solution isadded, and the mixture is made up to 2500 ml with water. To prepare unitdose forms, 1.0 or 2.5 ml are introduced into each glass ampoule, whichthen contains 50 or 125 mg, respectively, of active ingredient.

FORMULATION EXAMPLE 5

In a manner analogous to that described in the above FormulationExamples 1 to 4, it is also possible to prepare pharmaceuticalcompositions comprising a compound according to any one of PreparationExamples 1 to 25 or a compound having GABA_(B) -antagonistic propertiesthat is known per se, for example one of the compounds of formula Iproposed according to the invention for use as active ingredients inanti-epileptic medicaments, especially

3-aminopropyl(n-butyl)phosphine acid,

3-aminopropyl(diethoxymethyl)phosphinic acid,

3-aminopropyl(benzyl)phosphinic acid,

3-aminopropyl(1,1-difluorobutyl)phosphinic acid,

3-amino-2-(p-chlorophenyl)propyl(methyl)phosphinic acid,

3-amino-2-hydroxypropyl(cyclohexylmethyl)phosphinic acid,

3-(p-chlorobenzylamino)-2(R)-hydroxypropyl(benzyl)phosphinic acid,

3-amino-2(S)-hydroxypropyl(cyclohexylmethyl)phosphinic acid,

3-amino-2(S)-hydroxypropyl(benzyl)phosphinic acid,

3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid,

3-(p-chlorobenzylamino)-2-hydroxypropyl(n-butyl)phosphinic acid,

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(benzyl)phosphinic acid,

3-(3,4-dichlorobenzylamino)-2(S)-hydroxypropyl(diethoxymethyl)phosphinicacid, and

3-(p-chlorobenzylamino)propyl(cyclohexylmethyl)phosphinic acid,

or a pharmaceutically acceptable salt thereof.

PHARMACOLOGICAL EXAMPLE 1

Inhibition of "spike and wave" discharges in epileptic rats

Method: The action of GABA_(B) -antagonists was tested on male Wistarrats (300-400 g) of the Strasbourg colony. Animals of the 16th or 17thgeneration of the strain in which 100% of the test animals exhibit"spike and wave" discharges (epileptic rats) and animals of the 16th or17th generation of the strain in which 0% of the test animals exhibit"spike and wave" discharges (control strain) were used. The ratsreceived water and food ad libidum, and the light/dark cycle was 12/12hours. The rats were anaesthetised with pentobarbital (40 mg/kg i.p.)and implanted bilaterally with 4 stainless steel electrodes (two in thefrontal cortex and two in the parietal cortex). The rats were used forexperiments no sooner than one week after the operation.

The rats, which were freely mobile, were accommodated in a Plexiglasscage (17×17×28 cm) (one rat per cage), and after a 15-minute period foradaptation to the new surroundings, the EEG was recorded over a periodof 20 minutes (reference period). The reference line for the particulartest series is thus obtained. A GABA_(B) -antagonist was thenadministered and the EEG was recorded over a period of from 120 to 180minutes. The rats were kept under constant observation during thisperiod and prevent from falling asleep by gentle manual contact.

Test arrangement: The test compound was dissolved in 0.9% sodiumchloride solution and injected in doses of 50, 100, 200 and 400 mg/kgi.p.. Alternatively, the test compound may be administered in apolyethylene glycol, such as Tween® 80, (2 drops/10 ml of suspension ofthe test compound of 0.9% sodium chloride solution; the suspension ishomogenised at 40° for 10 minutes by means of ultrasound, injectionvolume: 2 ml/kg) i.p. or by means of a stomach probe p.o.. Testcompounds that are soluble with difficulty are advantageouslyadministered in solution in a mixture of dimethyl sulfoxide (not morethan 10% by volume) and 0.9% sodium chloride solution or in 45% aqueoushydroxypropyl-β-cyclodextrin solution. Each animal is treated with alldoses in a randomised sequence. The time between two treatments shouldbe at least 5 days. The mean values ±SEM of the sum total duration ofthe "spike and wave" discharges of 6 rats over a period of 20 minutesare recorded.

EVALUATION OF DATA

The sum total duration of the spike and wave discharges (in seconds) ismeasured for each 20-minute period of the EEG recording. Comparisonsbetween the treatment and the reference period are carried out by meansof non-parametric variance analysis of the groups concerned (Friedmantest). The control group and the treated groups are compared by means ofthe Wilcoxon test only when a significant difference between the twogroups is found in the Friedmann test. The dose-dependent decrease inthe "spike and wave" discharges is shown in the following tables. Thesignificances of the different according to Wilcoxon between dosesmarked by an asteriks and dose 0 corresponds to p<0,005.

    __________________________________________________________________________    3-Aminopropyl(diethoxymethyl)phosphinic accid (i.p.):                         Doses (mg/kg)                                                                            0     50    100   200   400                                        PERIODS (min)                                                                 0-20       322 ± 51                                                                         322 ± 53                                                                         251 ± 73                                                                         260 ± 44                                                                         264 ± 54                                20-40      362 ± 58                                                                         281 ± 58                                                                         193 ± 65                                                                         134 ± 22                                                                         105 ± 37                                40-60      393 ± 46                                                                         133 ± 40*                                                                        66 ± 44*                                                                         57 ± 26*                                                                         47 ± 20*                                60-80      336 ± 37                                                                         198 ± 28*                                                                        74 ± 59*                                                                         27 ± 16*                                                                         52 ± 44*                                80-100     337 ± 38                                                                         195 ± 32                                                                         195 ± 38                                                                         46 ± 21*                                                                         42 ± 28*                                100-120    377 ± 51                                                                         182 ± 43                                                                         127 ± 57                                                                         43 ± 12*                                                                         >22 ± 9*                                REFERENCE LINE                                                                           419 ± 33                                                                         377 ± 82                                                                         462 ± 74                                                                         452 ± 60                                                                         511 ± 53                                3-Aminopropyl(diethoxymethyl)phosphinic acid (p.o.):                          DOSE (mg/kg)                                                                             0     300   500                                                    PERIODS (min)                                                                 0-20       263 ± 36                                                                         91 ± 31*                                                                         123 ± 58                                            20-40      391 ± 60                                                                         182 ± 92                                                                         20 ± 10*                                            40-60      374 ± 86                                                                         227 ± 127                                                                        2 ± 1*                                              60-80      368 ± 58                                                                         122 ± 67                                                                         7 ± 5*                                              80-100     364 ± 44                                                                         85 ± 35*                                                                         0 ± 0*                                              100-120    347 ± 58                                                                         184 ± 86*                                                                        2 ± 1*                                              120-140    391 ± 60                                                                         239 ± 132*                                                                       2 ± 2*                                              140-160    364 ± 44                                                                         234 ± 117*                                                                       1 ± 1*                                              REFERENCE LINE                                                                           386 ± 52                                                                         356 ± 39                                                                         372 ± 64                                            3-Aminopropyl(n-butyl)phsophinic acid (i.p.):                                 DOSES (mg/kg)                                                                            0     50    100   200   400                                        PERIODS (min)                                                                 0-20       321 ± 48                                                                         219 ± 55                                                                         213 ± 25                                                                         192 ± 73                                                                         49 ± 21*                                20-40      353 ± 59                                                                         232 ± 45                                                                         58 ± 18*                                                                         73 ± 21*                                                                         13 ± 6*                                 40-60      299 ± 30                                                                         137 ± 34*                                                                        59`18*                                                                              40`19*                                                                              5`2*                                       60-80      327 ± 61                                                                         151 ± 34*                                                                        76 ± 30*                                                                         47 ± 22*                                                                         2 ± 1*                                  80-100     312 ± 55                                                                         227 ± 53                                                                         33 ± 12*                                                                         32 ± 30*                                                                         1 ± 1*                                  100-120    282 ± 39                                                                         258 ± 39                                                                         107 ± 40                                                                         95 + 45                                                                             0 ± 0*                                  120-140    197 ± 51                                                                         226 ± 41                                                                         135 ± 36                                                                         42 ± 25                                                                          2 ± 1*                                  140-160    219 ± 52                                                                         292 ± 39                                                                         92 ± 21                                                                          82 ± 44                                                                          1 ± 1*                                  160 ± 180                                                                             270 ± 44                                                                         309 ± 32                                                                         131 ± 29                                                                         58 ± 21*                                                                         2 ± 1*                                  REFERENCE LINE                                                                           369 ± 60                                                                         340 ± 60                                                                         435 ± 48                                                                         430 ± 58                                                                         425 ± 74                                3-Aminopropyl(n-butyl)phosphinic acid (p.o.):                                 DOSES (mg/kg)                                                                            0     300   500                                                    PERIODS (min)                                                                 0-20       263 ± 36                                                                         61 ± 23*                                                                         143 ± 45                                            20 -40     391 ± 60                                                                         65 ± 42*                                                                         134 ± 38                                            40-60      374 ± 86                                                                         108 ± 55                                                                         98 ± 26*                                            60-80      369 ± 58                                                                         102 ± 59                                                                         63 ± 16*                                            80-100     364 ± 44                                                                         73 ± 42*                                                                         36 ± 19*                                            100-120    347 ± 58                                                                         44 ± 18*                                                                         23 ± 15*                                            120-140    391 ± 60                                                                         26 ± 11*                                                                         9 ± 19*                                             140-160    364 ± 44                                                                         0 ± 0*                                                                           0 ± 0*                                              REFERENCE LINE                                                                           384 ± 52                                                                         231 ± 30                                                                         285 ± 53                                            3-Aminopropyl(cylcohexylmethyl)phosphinic acid (i.p.):                        DOSES (mg/kg)                                                                            0     25    50    100   200   400                                  PERIODS (min)                                                                 0-20       333 ± 39                                                                         163 ± 19                                                                         63 ± 20*                                                                         133 ± 37*                                                                        61 ± 18*                                                                         38 ± 23*                          20-40      385 ± 48                                                                         45 ± 15*                                                                         17 ± 7*                                                                          15 ± 3*                                                                          3 ± 3*                                                                           0 ± 0*                            40-60      312 ± 50                                                                         14 ± 5*                                                                          1 ± 1*                                                                           12 ± 3*                                                                          1 ± 1*                                                                           0 ± 0*                            60-80      392 ± 51                                                                         29 ± 8*                                                                          11 ± 5*                                                                          3 ± 2*                                                                           0 ± 0*                                                                           0 ± 0*                            80-100     392 ± 41                                                                         41 ± 6*                                                                          0 ± 0*                                                                           32 ± 7*                                                                          2 ± 2*                                                                           0 ± 0*                            100-120    262 ± 30                                                                         18 ± 8*                                                                          45 ± 22*                                                                         12 ± 5*                                                                          3 ± 2*                                                                           1 ± 1*                            REFERENCE LINE                                                                           383 ± 38                                                                         235 ± 26                                                                         361 ± 75                                                                         371 ± 66                                                                         463 ± 55                                                                         380 ± 77                          3-Aminopropyl(cyclohexylmethyl)phosphinic acid (p.o.):                        DOSES (mg/kg)                                                                            0     300                                                          PERIODS (min)                                                                 0-20       263 ± 36                                                                         124 ± 53                                                                         10 ± 6*                                             20-40      391 ± 60                                                                         157 ± 78                                                                         0 ± 0*                                              40-60      374 ± 86                                                                         162 ± 71                                                                         0 ± 0*                                              60-80      369 ± 58                                                                         75 ± 43                                                                          0 ± 0*                                              80-100     364 ± 44                                                                         116 ± 77                                                                         0 ± 0*                                              100-120    347 ± 58                                                                         21 ± 21*                                                                         0 ± 0*                                              120-140    391 ± 60                                                                         54 ± 38*                                                                         0 ± 0*                                              140-160    364 ± 44                                                                         47 ± 34*                                                                         0 ± 0*                                              REFERENCE LINE                                                                           386 ± 52                                                                         337 ± 37                                                                         426 ± 74                                            3-Aminopropyl(benzyl)phosphinic acid (i.p.):                                  DOSES (mg/kg)                                                                            0     50    100   200   400                                        PERIODS (min)                                                                 0-20       292 ± 57                                                                         223 ± 57                                                                         186 ± 43                                                                         12 ± 11*                                                                         7 ± 4*                                  20-40      306 ± 82                                                                         68 ± 30*                                                                         39 ± 26*                                                                         2 ± 1*                                                                           0 ± 0*                                  40-60      268 ± 15                                                                         114 ± 32*                                                                        39 ± 28*                                                                         1 ± 1*                                                                           0 ± 0*                                  60-80      326 ± 69                                                                         112 ± 34*                                                                        52 ± 30*                                                                         2 ± 3*                                                                           0 ± 0*                                  80-100     326 ± 73                                                                         140 ± 43                                                                         36 ± 13*                                                                         2 ± 1*                                                                           0 ± 0*                                  100-120    232 ± 55                                                                         162 ± 50                                                                         27 ± 17*                                                                         0 ± 0*                                                                           0 ± 0*                                  REFERENCE LINE                                                                           343 ± 68                                                                         393 ± 75                                                                         318 ± 49                                                                         307 ± 34                                                                         415 ± 73                                3-Amino-2-hydroxypropyl(cyclohexylmethyl)phosphinic acid (i.p.):              DOSES (mg/kg)                                                                            0     25    50    100   200   400                                  PERIODS (min)                                                                 0-20       294 ± 37                                                                         240 ± 67                                                                         192 ± 50                                                                         98 ± 43*                                                                         7 ± 7*                                                                           7 ± 5*                            20-40      227 ± 33                                                                         78 ± 47*                                                                         82 ± 44*                                                                         41 ± 29*                                                                         0 ± 0*                                                                           0 ± 0*                            40-60      276 ± 34                                                                         27 ± 8*                                                                          21 ± 9*                                                                          40 ± 39                                                                          1 ± 1*                                                                           1 ± 1*                            60-80      281 ± 40                                                                         35  ± 20*                                                                        8 ± 3*                                                                           16 ± 16*                                                                         1 ± 1*                                                                           3 ± 3*                            80-100     299 ± 14                                                                         6 ± 2*                                                                           15 ± 5                                                                           16 ± 16*                                                                         0 ± 0*                                                                           5 ± 5*                            100-120    293 ± 14                                                                         29 ± 14*                                                                         13 ± 5                                                                           17 ± 17*                                                                         0 ± 0*                                                                           5 ± 5*                            REFERENCE LINE                                                                           312 ± 36                                                                         305 ± 65                                                                         445 ± 74                                                                         315 ± 60                                                                         292 ± 26                                                                         310 ± 50                          3-Amino-2-hydroxypropyl(cyclohexylmethyl)phosphinic acid (p.o.):              DOSES (mg/kg)                                                                            0     300   500                                                    0-20       263 ± 36                                                                         176 ± 61                                                                         105 ± 29*                                           20-40      391 ± 60                                                                         103 ± 42*                                                                        149 ± 43                                            40-60      374 ± 86                                                                         95 '5 33*                                                                           117 ± 26*                                           60-80      369 ± 58                                                                         73 ± 22*                                                                         104 ± 26*                                           80-100     364 ± 44                                                                         46 ± 14*                                                                         56 ± 30*                                            100-120    347 ± 58                                                                         19 ± 12*                                                                         32 ± 12*                                            120-140    391 ± 60                                                                         73 ± 55*                                                                         40 ± 13*                                            140-160    364 ± 44                                                                         4 ± 4*                                                                           5 ± 4*                                              REFERENCE LINE                                                                           386 ± 52                                                                         220 ± 43                                                                         288 ± 46                                            3-Aminopropyl(cyclopropylmethyl)phosphinic acid (i.p.):                       DOSES (mg/kg)                                                                            0     100   200   400                                              PERIODS (min)                                                                 0-20       332 ± 78                                                                         292 ± 47                                                                         338 ± 71                                                                         199 ± 75                                      20-40      321 ± 47                                                                         252 ± 24                                                                         108 ± 54*                                                                        60 ± 34*                                      40-60      334 ± 62                                                                         107 ± 18*                                                                        100 ± 72*                                                                        7 ± 4*                                        60-80      358 ± 68                                                                         185 ± 51*                                                                        19 ± 12*                                                                         5 ± 3*                                        80-100     272 ± 37                                                                         117 ± 30*                                                                        90 ± 46*                                                                         2 ± 2*                                        100-120    339 ± 37                                                                         151 ± 40*                                                                        54 ± 27*                                                                         4 ± 1*                                        REFERENCE LINE                                                                           372 ± 64                                                                         392 ± 77                                                                         447 ± 66                                                                         352 ± 12                                      3-Aminopropyl(1,1-difluorobutyl)phosphinic acid (i.p.):                       DOSES (mg/kg)                                                                            0     100   200                                                    PERIODS (min)                                                                 0-20       267 ± 39                                                                         145 ± 57                                                                         219 ± 61                                            20-40      266 ± 38                                                                         63 ± 27*                                                                         71 ± 33*                                            40-60      273 ± 40                                                                         56 ± 27*                                                                         47 ± 18*                                            60-80      263 ± 37                                                                         99 ± 46*                                                                         16 ± 11*                                            80-100     264 ± 35                                                                         87 ± 47*                                                                         14 ± 13*                                            100-120    308 ± 41                                                                         36 ± 23*                                                                         18 ± 10*                                            REFERENCE LINE                                                                           307 ± 42                                                                         304 ± 72                                                                         297 ± 46                                            3-Aminopropyl(1-hydroxybenzyl)phosphinic acid (i.p.):                         DOSES (mg/kg)                                                                            0     100   200   400                                              PERIODS (min)                                                                 0-20       251 ± 56                                                                         235 ± 74                                                                         187 ± 80                                                                         49 ± 17*                                      20-40      273 ± 60                                                                         222 ± 55                                                                         78 ± 40*                                                                         16 ± 6*                                       40-60      306 ± 70                                                                         88 ± 20*                                                                         44 ± 21*                                                                         1 ± 1*                                        60-80      254 ± 48                                                                         167 ± 63                                                                         12 ± 6*                                                                          0 ± 0*                                        80-100     262 ± 54                                                                         130 ± 48                                                                         20 ± 10*                                                                         9 ± 4*                                        100-120    280 ± 57                                                                         95 ± 25*                                                                         14 ± 10                                                                          7 ± 2*                                        REFERENCE LINE                                                                           306 ± 45                                                                         320 ± 34                                                                         298 ± 36                                                                         248 ± 23                                      3-Amino-2(S)-hydroxypropyl(cyclohexylmethyl)phsophinic acid (i.p.):           DOSES (mg/kg)                                                                            0     25    100                                                    PERIODS (min)                                                                 0-20       286 ± 47                                                                         206 ± 48                                                                         240 ± 60                                            20-40      310 ± 64                                                                         97 ± 19*                                                                         12 ± 5*                                             40-60      342 ± 69                                                                         49 ± 23*                                                                         6 ± 4*                                              60-80      285 ± 47                                                                         23 ± 14*                                                                         2 ± 1*                                              80-100     282 ± 54                                                                         4 ± 3*                                                                           4 ± 3*                                              100-120    301 ± 49                                                                         9 ± 5*                                                                           3 ± 2*                                              REFERENCE LINE                                                                           341 ± 43                                                                         402 ± 58                                                                         548 ± 38                                            3-(3,4-Dichlorobenzylamino)propyl(diethoxymethyl)phosphinic acid (i.p.):      DOSES (mg/kg)                                                                            0     100   200   400                                              PERIODS (min)                                                                 0-20       321 ± 50                                                                         119 ± 49                                                                         148 ± 65                                                                         310 ± 73                                      20-40      292 ± 92                                                                         151 ± 33                                                                         166 ± 92                                                                         45 ± 25*                                      40-60      363 ± 96                                                                         270 ± 68                                                                         161 ± 103                                                                        75 ± 44*                                      60-80      313 ± 45                                                                         151 ± 27                                                                         200 ± 112                                                                        100 ± 71*                                     80-100     326 ± 52                                                                         261 ± 60                                                                         183 ± 110                                                                        58 ± 363                                      100-120    328 ± 72                                                                         205 ± 40                                                                         218 ± 58                                                                         76 ± 48*                                      REFERENCE LINE                                                                           348 ± 58                                                                         271 ± 64                                                                         420 ± 48                                                                         424 ± 55                                      __________________________________________________________________________

PHARMALOGICAL EXAMPLE 2

Inhibition of the "spike and wave" discharges induced by "grand mal"anti-epileptics in epileptic rats.

METHOD AND TEST ARRANGEMENT

The method and test arrangement correspond to those of PharmacologicalExample 1.

3-Aminopropyl(diethoxymethyl)phosphinic acid: Antagonism of the "spikeand wave" discharges induced by carbamaepine.3-Aminopropyl(diethoxymethyl)phosphinic acid was administered at time 0,and 20 mg/kg of carbamazepine were administered at time 40, in each casei.p..

    ______________________________________                                        DOSES (mg/kg) 0         200       400                                         ______________________________________                                        PERIODS (min)                                                                 0-20          289 ± 43                                                                             353 ± 53                                                                             115 ± 43                                 20-40         324 ± 46                                                                             178 ± 37                                                                             93 ± 71*                                 40-60         636 ± 43                                                                             173 ± 78*                                                                            23 ± 14*                                 60-80         669 ± 14                                                                             70 ± 64*                                                                             29 ± 29*                                 80-100        675 ± 75                                                                             18 ± 17*                                                                             9 ± 9*                                   REFERENCE LINE                                                                              337 ± 58                                                                             357 ± 30                                                                             310 ± 69                                 ______________________________________                                    

3-Aminopropyl(diethosymethyl)phosphinic acid: Antagonism of the "spikeand wave" discharges induced by phenytoin.3-Aminopropyl(diethoxymethyl)phosphinic acid was administered at time 0,and 20 mg/kg of phenytoin were administered at time 40, in each casei.p..

    ______________________________________                                        DOSES (mg/kg) 0         200       400                                         ______________________________________                                        PERIODS (min)                                                                 0-20          382 ± 62                                                                             394 ± 87                                                                             139 ± 61                                 20-40         330 ± 58                                                                             172 ± 64                                                                             48 ± 40                                  40-60         555 ± 24                                                                             124 ± 85*                                                                            31 ± 31*                                 60-80         658 ± 27                                                                             239 ± 70*                                                                            56 ± 53*                                 80-100        562 ± 76                                                                             95 ± 37*                                                                             42 ± 39*                                 REFERENCE LINE                                                                              371 ± 23                                                                             430 ± 61                                                                             4971 ± 68                                ______________________________________                                    

3-Aminopropy(diethoxymethyl)phosphinic acid: Antagonism of the "spikeand wave" discharges induced by Vigabatrin®.3-Aminopropyl(diethoxymethyl)phosphinic acid was administered at time 0,and 20 mg/kg of Vigabatrin® were administered at time 160, in each casei.p..

    ______________________________________                                        DOSES (mg/kg) 0         200       400                                         ______________________________________                                        PERIODS (min)                                                                 240-260       875 ± 63                                                                             213 ± 52*                                                                            44 ± 13*                                 260-280       938 ± 65                                                                             249 ± 57*                                                                            28 ± 8*                                  REFERENCE LINE                                                                              408 ± 68                                                                             310 ± 34                                                                             363 ± 44                                 ______________________________________                                    

What is claimed is:
 1. A method for the treatment of epilepsies of thepetit mal type and for suppressing petit-mal type conditions which mayarise in the case of treatment with known anti-epileptics, in awarm-blooded organism in need thereof which comprises administering tosuch warm-blooded organism at least one compound having GABA_(B)-antagonistic properties of formula I ##STR24## wherein one of theradicals R₁, R₂ and R₃ is hydrogen or an aliphatic, cycloaliphatic,araliphatic or aromatic radical, another is hydrogen or, in the case ofR₁ or R₂, hydroxy or, in the case of R₁, halogen or, in the case of R₂together with R₂ ', oxo, and the remaining radical is hydrogen, R₁ ' ishydrogen or halogen, R₂ ' is hydrogen, hydroxy or, together with R₂, isoxo, R₄ and R₅ are hydrogen and R is an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, araliphatic, heteroarylaliphatic or aromaticradical having at least 2 carbon atoms or, when R₁ is hydrogen orhydroxy, R₂ is an aromatic radical and R₁ ', R₂ ' and R₃ are hydrogen, Ris methyl, or a pharmaceutically acceptable salt thereof.
 2. A method oftreatment according to claim 1 wherein one of the radicals R₁, R₂ and R₃is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, orphenyl-lower alkyl, diphenyl-lower alkyl or naphthyl-lower alkyl each ofwhich is unsubstituted or mono- or poly-substituted in the phenyl ornaphthyl moiety by lower alkyl, lower alkoxy, halogen and/or bytrifluoromethyl, or phenyl or naphthyl each of which is unsubstituted orsubstituted by halogen, lower alkyl, lower alkoxy and/or bytrifluoromethyl, another radical is hydrogen or, in the case of R₁ orR₂, hydroxy or, in the case of R₁, halogen or, in the case of R₂together with R₂ ', oxo, and the remaining radical is hydrogen, R₁ ' ishydrogen or halogen, R₂ ' is hydrogen, hydroxy or, together with R₂, isoxo, R₄ and R₅ are hydrogen, and R is lower alkyl having at least 2carbon atoms, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkyl-loweralkyl, cycloalkenyl-lower alkyl, mono-, di- ortrihydroxycycloalkyl-lower alkyl, cycloalkyl(hydroxy)-lower alkyl,(lower alkylthio)cycloalkyl(hydroxy)-lower alkyl, or phenyl- ornaphthyl-lower alkyl each of which is unsubstituted or mono- orpoly-substituted in the phenyl or naphthyl moiety by lower alkyl, loweralkoxy, halogen and/or by trifluoromethyl, or phenyl or naphthyl each ofwhich is unsubstituted or substituted by halogen, lower alkyl, loweralkoxy and/or by trifluoromethyl, or when R₁ is hydrogen or hydroxy, R₂is an aromatic radical and R₁ ', R₂ ' and R₃ are hydrogen, R is methyl,or a pharmaceutically acceptable salt thereof.
 3. A method of treatmentaccording to claim 1 wherein one of the radicals R₁, R₂ and R₃ ishydrogen, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, phenyl-C₁ -C₄ alkyl that isunsubstituted or mono- or poly-substituted in the phenyl or naphthylmoiety by C₁ -C₄ alkyl, C₁ -C₄ alkoxy, halogen and/or bytrifluoromethyl, or is phenyl that is unsubstituted or mono- orpoly-substituted in the phenyl or naphthyl moiety by C₁ -C₄ alkyl, C₁-C₄ alkoxy, halogen and/or by trifluoromethyl, another radical ishydrogen or, in the case of R₁ or R₂, hydroxy, and the remaining radicalis hydrogen, R₁ ' is hydrogen, R₂ ' is hydrogen, hydroxy or, togetherwith R₂, is oxo, R₄ and R₅ are hydrogen, and R is C₂ -C₇ -alkyl,α,α-di-C₁ -C₄ alkoxy-C₂ -C₇ alkyl, α,α-dihalo-C₂ -C₇ alkyl, C₃ -C₆cycloalkyl, C₃ -C₆ cycloalkyl-C₁ -C₄ alkyl, C₃ -C₈ -cycloalkenyl-C₁ -C₄-alkyl, mono-, di- or trihydroxy-C₃ -C₈ -cycloalkyl-C₁ -C₄ -alkyl, C₃-C₈ cycloalkenyl-C₁ -C₄ alkyl, mono-, di- or trihydroxy-C₃ -C₈cycloalkyl-C₁ -C ₄ alkyl, benzyl or, when R₂ is halophenyl and R₁, R₁ ',R₂ ' and R₃ are hydrogen, R is methyl, or a pharmaceutically acceptablesalts thereof.
 4. A method of treatment according to claim 1 wherein R₁,R₁ ', R₂ ' and R₃ are hydrogen, R₂ is hydrogen or hydroxy, R₄ and R₅ arehydrogen, and R is C₂ -C₇ alkyl, α,α-di-C₁ -C₄ alkoxy-C₁ -C₄ alkyl,α,α-dihalo-C₂ -C₇ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkyl-C₁ -C₄alkyl, α-(C₃ -C₆ cycloalkenyl)-C₁ -C₄ alkyl, α-(mono-, di- ortrihydroxy-C₃ -C₆ cycloalkyl)-C₁ -C₆ cycloalkyl)-C₁ -C₄ alkyl or is aphenyl-C₁ -C₄ alkyl radical that is unsubstituted or mono- orpoly-substituted in the phenyl moiety by C₁ -C₄ alkyl, C₁ -C₄ alkoxy,halogen and/or by trifluoromethyl, or a pharmaceutically acceptable saltthereof.
 5. A method of treatment according to claim 1 wherein saidcompound of formula I is 3-aminopropyl(cyclohexylmethyl)phosphinic acidor a pharmaceutically acceptable salt thereof.
 6. A method of treatmentaccording to claim 1 wherein said compound of formula I is3-aminopropyl(n-butyl)phosphinic acid or a pharmaceutically acceptablesalt thereof.
 7. A method of treatment according to claim 1 wherein saidcompound of formula I is 3-aminopropyl(diethoxymethyl)phosphinic acid ora pharmaceutically acceptable salt thereof.
 8. A method of treatmentaccording to claim 1 wherein said compound of formula I is3-aminopropyl(benzyl)phosphinic acid or a pharmaceutically acceptablesalt thereof.
 9. A method of treatment according to claim 1 wherein saidcompound of formula I is 3-aminopropyl(1,1-difluorobutyl)phosphinic acidor a pharmaceutically acceptable salt thereof.
 10. A method of treatmentaccording to claim 1 wherein said compound of formula I is3-amino-2-hydroxypropyl(cyclohexylmethyl)phosphinic acid or apharmaceutically acceptable salt thereof.
 11. A method of treatmentaccording to claim 1 wherein said compound of formula I is3-amino-2(S)-hydroxypropyl)cyclohexylmethyl)phosphinic acid or apharmaceutically acceptable salt thereof.
 12. A method of treatmentaccording to claim 1 wherein said compound of formula I is3-amino-2(S)-hydroxypropyl(benzyl)phosphinic acid or a pharmaceuticallyacceptable salt thereof.
 13. A method of treatment according to claim 1wherein said compound of formula I is 3-aminopropyl(benzyl)phosphinicacid or a pharmaceutically acceptable salt thereof.